KR20050054857A - Process for obtaining vitamin d derivatives from monohalogenovinyl compounds - Google Patents

Abstract

A reaction comprising reacting a (C20) -monohalogenovinyl derivative with a metal or organometallic reagent, and then reacting with another active reagent.

A novel method of obtaining a vitamin D derivative of is disclosed.

Description

Process for obtaining vitamin D derivatives from monohalogenovinyl compounds

The present invention comprises the step of reacting a (C20) -monohalogenovinyl compound (monohalogenovinyl compound) of general formula (II) with a metal or organometallic reagent, and then reacting with another suitable reagent A method for obtaining vitamin D derivatives of general formula (I). The present invention is also directed to different therapeutic fields, such as the treatment and / or prophylaxis of metabolic bone disease, diseases characterized by changes in cell differentiation and proliferation (dermatology and oncology) and the like. A useful or potentially useful method for using a compound of general formula (II) to obtain a vitamin D derivative of general formula (I).

(I)

(II)

Both cyclic and ring-opening steroidal chemistries are complex chemistries that result from the simultaneous generation of different functional groups and several chiral centers in the molecule, thereby giving higher selectivity and specificity in the reaction product. Special attention has been paid to reactions and reagents.

Vitamin D derivatives such as tacalcitol, calcipotriol, floccaltriol, 22-oxacicitriol, cecaliferol and the like are characterized by changes in metabolic bone disease, cell differentiation and proliferation (dermatology and oncology), for example. It is a steroidal compound that has been used or developed in different therapeutic fields such as disease.

Referring to the chemical structure of vitamin D ₂ below,

The above-mentioned derivatives are mainly derived from the somewhat severe alteration of the C20 side chain, and also other monohydroxylated or dehydroxylated alterations with respect to the C1 and C3 positions.

Interest in analogues has been derived from the fact that 1α, 25-dihydroxyvitamin D ₃ (calcitriol) is a vitamin D ₃ metabolite with hormonal activity.

In recent years, in addition to interest in 25-hydroxy analogues, hormonal activity has been attributed to the translocation of 25-hydroxyl to the 24 or 26 position and C22-C23 (vitamin D ₂ itself already has such double bonds). Can be controlled by introducing a double bond between positions or by introducing a triple bond to C22, which is the same position, and interest in C22-C23 alkyne analogues arises accordingly.

In many cases, these unsaturated derivatives are used as precursors of saturated derivatives, since saturated derivatives can be obtained simply by hydrogenation of unsaturated derivatives. As a result, C22-C23 saturated derivatives are also given importance.

Significant therapeutic interest is focused on C24 hydroxylated vitamin D derivatives, particularly due to the low tendency to induce hypercalcemia, to the extent that they do not break out or are induced with low intensity, in C25 hydroxylated derivatives. Examples of C24 derivatives are cecaliferol used to treat osteoporosis, tacalcitol and calcipotriol both used as therapeutic agents for psoriasis.

Thus, the hydroxylation of other carbons in the C20 side chain, the formation of C22-C23 double or triple bonds, together with the corresponding saturated derivatives, are important for the chemistry of vitamin D.

Formation of C22-C23 double bonds in vitamin D chemistry is generally performed in the Wittig or Wittig-Horner reaction, the aldol reaction, or the Julia-Ligogo olefination reaction. Lythgoe olefination reaction) is carried out from aldehyde (III) (Carverley: Tetrahedron , Vol. 43, No. 20, 4609 (1987) and WO87 / 00834-A; Hesse: EP0078704) C20 aldehyde (IV). Since trans having pharmacological activity in the stereochemistry of the double bond is trans , other methods of obtaining cis , or cis-trans mixtures, will only be useful if the subsequent reaction is a hydrogenation reaction to obtain a saturated derivative.

The formation of C22-C23 triple bonds is also carried out from the aldehydes of formula (III) by the Wittig reaction with polyhalogenated methane derivatives (WO 92/03414).

(IV)

(III)

One of the most serious disadvantages of these methods is the deprotection of the aldehyde of formula (III) to the compound of formula (IV), which leads to a particular isomerization of C20 carbonyl (5% or more depending on the conditions). In a weak alkaline medium. Separation of epimers generally takes place once the chain is introduced, but separation can be difficult when industrially produced.

On the other hand, there may be an additional increase in C20 epimers in the Wittich-Horner, Aldol and Julia-Lisgo reactions carried out in alkaline media. Therefore, there will be considerable interest in methods for stretching the C20 side chain while minimizing C20 epimer formation.

In the Wittich or Wittich-Horner reaction, double bonds with a trans configuration are formed when there is a C24 carbonyl functional group or unsaturated, giving conjugated enons and dienes, respectively, and the trans-cis mixture is generally such a functional group They are formed when they do not exist. However, this reaction may show high yields for compounds with one C24 carbonyl ( Tetrahedron , Vol. 43, No. 20, 1987) or low yields (CA 2026671). For Julia- Lisgo Olefination ( Journal Organic Chemistry , 53, 3450 (1988)), low yields are generally shown. In addition, this olefination is not suitable on an industrial scale since there is a process of desulfurizing the sulfone intermediate with sodium amalgam. On the other hand, deprotection of the aldehyde of formula (III) with the compound of formula (IV), which is a reaction showing a suitable yield, is also a matter to be considered.

From enones consisting of a Wittich or aldol reaction, C24 alcohols can generally be obtained by reduction or reaction with organometallics. In the case of reduction, partial reduction of the double bond occurs, which leads to a decrease in yield. If NaBH ₄ / CeCl ₃ reagent is used, the saturated alcohol is reduced by 1%, but the S / R ratio of C24 epimer alcohol is generally shown to be advantageous for inert R epimers. When using lithium and aluminum hydroxides mixed with chiral or achiral alcohols, higher S / R ratios are obtained, but some by-products are also formed that reduce the overall yield (double bond reduction, OH to H). Substitution, etc.). Chiral reagents, on the other hand, are generally very expensive and therefore somewhat inappropriate at an industrial scale.

According to the method disclosed in Synlett , 157 (1990), the compound of formula (IV) is converted into selenoacetal and reacted with chiral hydroxyaldehyde to introduce a C22-C23 unsaturated chain into a single C24 epimer. It is also possible. However, this method produces mainly C23-C24 cis alkenes with low yields.

Schemes of the above reaction

In order to introduce the hydroxy group to a further position (C25 or C26), a Julia-lisgo olefination reaction is often used, the main drawback of which is that the yield is obtained moderately ( J. Org. Chem . 58, 1496, 1993). Another route is also the Wittich reaction, which proceeds with good yield only in the formation of conjugated dienes with C26 carbonyl, which dienes are reacted with organometallic reagents and converted to hydroxy groups (WO 91/00855). If there is saturated carbon in the 24-25 position, the yield is low and a significant amount of cis isomer of C22-C23 double bond is obtained.

Obtaining alkenes from the corresponding C22-C23 alkyne by reduction of triple bonds is disclosed only to obtain cis double bonds ( Bioorganic & Medical Chemistry Letters , Vol. 3, 1841-1844 (1993)).

It should also be emphasized that the reagents of the Wittich, Wittich-Horner and Julia-Lisgo reactions are generally not commercial reagents, but often have to be synthesized at various stages and the entire process is expensive ( J. Org. Chem . 51, 4819, 1986; Chemical Reviews , 89, 863, 1989; Tetrahedron , 43, 20, 4609, 1987).

C20 alkyne preparations have been disclosed from the dihalogenovinyl derivatives Va (X = Cl) and Vb (X = Br) which react with n- BuLi.

(V)

Lithium acetylides formed can be reacted in situ with an electrophilic reagent or hydrolyzed with water to reveal an S batch in C20 ( Bioorganic & Medicinal Chemistry Letters , 13, 9, 1841 (1993)), with an R batch in C20 ( WO 92/03414) to obtain the corresponding alkyne.

Of type (V) Dihalogenated compounds are obtained from deprotected aldehydes, whereby unavoidable C20 isomerization also occurs in this case in connection with the references made when discussing C20 alkene acquisition.

Another disadvantage of the method lies in the fact that the conversion of compound (V) to lithium acetylide must proceed with a very accurate amount of n- BuLi, which, if excess is used, adds to the vitamin D backbone. Caused by.

In one aspect of the invention, the preparation of a C20 alkyne from an iodine derivative of formula (II) is described above, according to the fact that the deprotection of the iodine derivative is carried out without racemization, which also does not occur in the alkyne synthesis method. One disadvantage is solved.

On the other hand, the use of LDA or t- BuOK to obtain alkyne allows the use of excess reagents while preventing excess reagents from being added to the vitamin D backbone.

Alkynes having C24 oxo or hydroxy groups prepared in the present invention are already known ( Bioorganic Medicinal Chemistry Letters , 13, 9, 1841 (1993)), but they are obtained from compound (Va). However, routes provided in the present invention have not been disclosed previously.

As a result, high or thorough stereoselectivity and high yield properties are combined with respect to the trans configuration of the double bond between C22 and C23, with the property of having fewer by-products and commercially obtainable reagents, and the preferred C24 R configuration and the corresponding C25 And a new route to obtain hydroxylated vitamin D derivatives in the C24, C25 or C26 side chains, which provides a more favorable ratio of C26 batches.

The present invention is to solve the above problems, the present invention is to synthesize a vitamin D derivative in accordance with a simpler method to increase stereoselectivity, to obtain a vitamin D derivative of formula (I) to minimize by-products and impurities after synthesis It is an object to provide a method.

Summary of the Invention

The authors of the present invention disclose that the novel compounds of formula (II) disclosed in co-application patent application No. 200302806 with monohalovinyl groups as side chains bonded to C20 have better yields and higher stereoselectivity, methodological simplicity and more It has been found that new synthetic routes are possible that can provide pharmacologically useful vitamin D derivatives that exhibit fewer byproducts or impurities.

More specifically, the method presented by the present invention has the following advantages among the most outstanding properties, especially in its industrial manufacture:

The stereochemistry of the C22-C23 trans bond is maintained.

Isomerization of the new alkyne formed (C24-C25) is also trans .

At no stage does C20 racemization occur at a meaningful level.

The chain forming reaction generally proceeds at high yields.

In many cases, the reagents are commercially available and do not need to be converted into active derivatives (as sulfones in the case of the Witti reaction or as sulfones in the case of the Julia-Lisgo reaction).

In the case of the preparation of C24 hydroxy groups, the preparation of C24 S / R epimers can be carried out using NaBH ₄ / CeCl ₃ with C24 carbonyl when methods 3.1, 3.3 and 3.4 are used (see detailed description of the invention). Higher than the ratio obtained by reduction (1 / 1.5) 1: 1; However, the above mentioned ratio will reach 9/1 when Method 3.2 is used with propargyl alcohol prepared by reducing ketones with alpin-borane, 2.5 / l when used with Dip-chloride, S The minimum value of the / R ratio is 1/1.

In the case of C26 chiral alcohols, it is easy to obtain single isomers with optically pure (often commercial) allyl or propargyl alcohol as starting material (methods 5/01 and 6B / 2).

Therefore, the use of novel monohalogenovinyl compounds of formula (II) as starting materials for the preparation of vitamin D derivatives of formula (I) constitutes the object of the present invention.

In addition, the above-described method for converting the monohalogenovinyl compound of formula (II) to the vitamin D derivative of formula (I) also constitutes an object of the present invention.

The alkenylmonohalo derivatives of the above-mentioned formula (II) can be used to prepare various organometallic compounds by substituting metals with halogens used to form new C-C bonds.

Thus, to explain, the substitution with lithium or magnesium and its subsequent carbonyl compounds give access to various allyl alcohols. The present reaction can also be carried out with Cr ²⁺ (Nozaki reaction); Substitutions with palladium, on the other hand, include the Kumada reaction, the Negishi reaction, the Stille reaction, the Suzuki reaction, the Heck reaction, and the Sonogashira reaction. according to the reaction, it is possible to prepare polyene / polyphosphate by reaction with alkenes or alkynes, and with other organometallics to obtain monoalkenes.

For example, the elimination of halogen from compounds of formula (I) with LDA or t- BuOK / DMSO allows the preparation of alkanes, the subsequent reaction of which with carbonyl compounds and epoxides to various hydroxyalkynes. Make it accessible.

Subsequent reaction of the obtained product makes it possible for example to: obtain new alkenes from alkynes by reduction; Preparation of hydroxylated derivatives from carbonyl compounds; And obtaining a saturated derivative by hydrogenation of the side chain formed.

Detailed description of the invention

Vitamin D derivatives obtainable from formula (II) include the following general formula (I)

(I)

Corresponds to

In the formula,

A is a general formula (A1) Selected from (A2) and a residue of formula (A3):

(A1) (A2) (A3)

In the formula,

Z and Z 'are independently of each other hydrogen; Hydroxyl; Or a hydroxyl protective group protected with a hydroxyl protecting group;

W is a dienophile, preferably SO ₂ and 4-phenyl-1,2,4-triazolin-3,5-dione; And di-acid azo, such as phthalazine-1,4-dione; And

R ' ₁ , R' ₂ and R ' ₃ are each independently hydrogen; halogen; Hydroxyl; Hydroxyl protected with a hydroxyl protecting group; C ₁ -C ₆ alkyl optionally substituted with halogen, hydroxyl, cyano or amino; C ₂ -C ₆ alkenyl optionally substituted with halogen, hydroxyl, cyano or amino; Di (C ₁ -C ₃ ) alkyl ethers; Or C ₁ -C ₅ alkyl amino;

R ₁ , R ₂ , R ₃ and R ₄ are, independently from each other, hydrogen; C ₁ -C ₈ alkyl; C ₃ -C ₆ cycloalkyl; Or C ₆ -C ₁₄ aryl;

D is

Hydrogen;

In which R ₅ and R ₆ are, independently of each other, hydrogen; C ₁ -C ₈ alkyl; C ₃ -C ₆ cycloalkyl; C ₆ -C ₁₄ aryl; Or a ROR ₇ group in which R ₇ is hydrogen; C ₁ -C ₈ alkyl; C ₃ -C ₆ cycloalkyl; Or C ₆ -C ₁₄ aryl; And Y is hydrogen; Hydroxyl; Hydroxyl protected with a hydroxyl protecting group; Or wherein R ₇ is CR ₅ R ₆ Y, which is a group of -OR ₇ having the same meaning as described above; or

In which R ₅ is C (O) R ₅ having the same meaning as described above;

m is an integer selected from 0, 1 and 2;

n is an integer selected from 0 and 1;

p is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

At least one of "m", "n", or "p" is 0, and the sum of "m", "n", and "p" is equal to or greater than 1 ("m" + "n" + "p" ≥ 1).

As used herein, the term "hydroxyl protecting group" includes any functional group capable of protecting the hydroxyl group. Examples of hydroxyl group protecting groups are Ed. John Wiley & Sons, "Protective Groups in Organic Synthesis" 3rd edition (1999) (ISBN 0-471-16019-9), was disclosed by Green TW et al. Although substantially any hydroxyl protecting group can be used, in certain embodiments, the hydroxyl protecting group is a silyl derivative, such as t -butyldimethylsilyl (TBDMS), sometimes referred to herein as STBDM or MDBTS, for example, The hydroxyl group is protected by forming a silyl-ether by a protecting group, or the hydroxyl protecting group is an acyl group derived from a carboxylic acid such as an acetyl group (Ac) [CH ₃ -C (O)-] whereby the hydroxyl group is for example And in the form of carboxylic esters such as acetic acid esters.

The term C ₁ -C ₆ "alkyl" refers to a radical derived from a linear or branched alkan of 1 to 6 carbon atoms. Similarly, the term C ₁ -C ₅ "alkyl" refers to a radical derived from a saturated linear or branched hydrocarbon of 1 to 5 carbon atoms, while C ₁ -C ₈ "alkyl" The term "refers to radicals derived from saturated linear or branched hydrocarbons of 1 to 8 carbon atoms.

The term C ₂ -C ₆ "alkenyl" refers to a radical derived from a linear or branched alken of 2 to 6 carbon atoms.

The term C ₃ -C ₆ "cycloalkyl" refers to a radical derived from 3 to 6 carbon atoms.

The term C ₆ -C ₁₀ "aryl" refers to a radical derived from an aromatic hydrocarbon of 6 to 10 carbon atoms, due to the hydrogen loss of the central carbon atom. Similarly, the term C ₆ -C ₁₄ "aryl" refers to a radical derived from an aromatic hydrocarbon of 6 to 14 carbon atoms, due to the hydrogen loss of the central carbon atom.

Vitamin D derivatives of formula (I) are optionally substituted in the side chain as well as functional groups present in (D) and / or in the presence (or otherwise) of unsaturated (double and / or triple bonds) Different classes of compounds depending on the presence (or otherwise) of methylene.

One class of vitamin D derivatives of formula (I) includes compounds of formula (I) wherein m = 0, n = 0 and p ≠ 0 (ie p is an integer selected from 1 and 6).

Another class of vitamin D derivatives of formula (I) includes compounds of formula (I) wherein m = 0, n ≠ 0 (ie, n is an integer comprising between 1 and 3) and p = 0.

Another class of vitamin D derivatives of formula (I) is m = 0, n ≠ 0 (ie, n is an integer comprising between 1 and 3) and p ≠ 0 (ie, p is an integer selected from 1 and 6) Is a compound of formula (I).

Another class of vitamin D derivatives of formula (I) includes compounds of formula (I) wherein m ≠ 0 (ie, m is 1 or 2), n = 0 and p = 0.

Another class of vitamin D derivatives of formula (I) are m ≠ 0 (ie, m is 1 or 2), n ≠ 0 (ie, an integer comprising between 1 and 3), and p = 0 It includes the compound of (I).

Another class of vitamin D derivatives of formula (I) are m ≠ 0 (ie, m is 1 or 2), n = 0 and p ≠ 0 (ie, p is an integer between 1 and 6). Compound.

Vitamin D derivatives of formula (I) obtainable by the process of the invention are as follows:

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(ethynyl) -9,10-secopregna-5 ( E ),-7 ( E ), 10 (19) -triene (Compound 1);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(ethynyl) -9,10-secopregna-5 ( Z ),-7 ( E ), 10 (19) -triene (Compound 2);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3'-oxopropyn-1'-yl) -9,10- Cecopregna-5 ( E ),-7 ( E ), 10 (19) -triene (Compound 3);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3'-oxopropyn-1'-yl) -9,10- Cecopregna-5 ( Z ),-7 ( E ), 10 (19) -triene (Compound 4);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3 '-( R ) -hydroxypropyn-1'-yl) -9,10-secopregna-5 ( E ),-7 ( E ), 10 (19) -triene (Compound 5 ( R ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3 '-( S ) -hydroxypropyn-1'-yl) -9,10-secopregna-5 ( E ),-7 ( E ), 10 (19) -triene (Compound 5 ( S ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3 '-( R ) -hydroxypropyn-1'-yl) -9,10-secopregna-5 ( Z ),-7 ( E ), 10 (19) -triene (Compound 6 ( R ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3 '-( S ) -hydroxypropyn-1'-yl) -9,10-secopregna-5 ( Z ),-7 (E), 10 (19) -triene (Compound 6 ( S ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(4'-hydroxy-4'-methylpentin-1'-yl) -9,10-year old Copregna-5 ( E ),-7 ( E ), 10 (19) -triene (Compound 7);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-hydroxy-4'-methylpent-1'-ynyl) -9,10-three SO ₂ addition product of copregna-5,7 ( E ), 10 (19) -triene (Compound 8);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-hydroxy-3 '( R ) -isopropylpro-pan-1'-yl) -9,10-secopregna-5 ( E ),-7 ( E ), 10 (19) -triene (Compound 9 ( R ));

-1 (S), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-hydroxy-3 '( S ) -isopropylpropane-1'-yl) -9 , 10-secopregna-5 ( E ),-7 ( E ), 10 (19) -triene (Compound 9 ( S ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-hydroxy-4'-methylpentan-1'-yl) -9,10-three Copregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 10);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-oxo-pentane-1'-yl) -9,10-secopregnna-5, SO ₂ addition product of 7 ( E ), 10 (19) -triene (Compound 11);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-oxopentan-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 12);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(butan-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 13);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-methylpentan-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 14);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-hydroxyl-5'-methylpentan-1'-yl) -9,10-three SO ₂ addition product of copregna-5,7 ( E ), 10 (19) -triene (Compound 15);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-oxo-pent-1 '( E ) -enyl) -9,10-secopregnna SO ₂ addition product of -5,7 ( E ), 10 (19) -triene (Compound 16);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(butene-1 '( E ) -yl) -9,10-secopregna-5 ( E ) , 7 ( E ), 10 (19) -triene (Compound 17);

-1 (S), 3 (R ) - bis (tert-butyldimethylsilyloxy) -20 (R) - (4'- methyl pentene -1 'E) - yl) -9,10-secopregna -5 ( E ), 7 ( E ), 10 (19) -triene (Compound 18);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxyprop-1' ( E )- Enyl) -9,10-seco-pregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 19 ( R ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E )- Enyl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 19 ( S ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-dimethyl-3 '( R ) -hydroxypenta-1' ( E ) -enyl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 20 ( R ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-dimethyl) -3 '( S ) -hydroxypenta-1' ( E ) -enyl ) -9,10-Secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 20 ( S ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxyprop-1' ( E )- Enyl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (Compound 21 ( R ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E )- Enyl) -9,10-seco-pregna-5 ( Z ), 7 ( E ), 10 (19) -triene (Compound 21 ( S ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( R ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (Compound 22 ( R ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( S ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (Compound 22 ( S ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-cyclohexyl-3 '( R ) -hydroxyprop-1' ( E )- Enyl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 23 ( R ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-cyclohexyl-3 '( S ) -hydroxyprop-1' ( E )- Enyl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 23 ( S ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( R ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 24 ( R ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( S ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 24 ( S ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-cyclohexyl-3 '( R ) -hydroxyprop-1' ( E )- Enyl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 25 ( R ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-cyclohexyl-3 '( S ) -hydroxyprop-1' ( E )- Enyl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 25 ( S ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'dimethyl-3 '( R ) -hydroxypent-1' ( E ) -enyl)- 9,10-Secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (Compound 26 ( R ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'dimethyl-3 '( S ) -hydroxypent-1' ( E ) -enyl)- 9,10-Secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (Compound 26 ( S ));

-20 ( R )-(3'-cyclopropyl-3 '(R) -hydroxyprop-1' ( E ) -enyl) -1 ( S ), 3 ( R ) -dihydroxy-9,10 -Se-copregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 27 ( R ));

-20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -1 ( S ), 3 ( R ) -dihydroxy-9,10 Secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (Compound 27 ( S ));

-20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxyprop-1' ( E ) -enyl) -1 ( S ), 3 ( R ) -dihydroxy-9,10 -Se-copregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 28 ( R ));

-20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -1 ( S ), 3 ( R ) -dihydroxy-9,10 Secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 28 ( S ));

-1 ( S ), 3 ( R ) -dihydroxy-20 ( R )-(3 '(S) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-seco Pregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 29 ( R ));

-1 ( S ), 3 ( R ) -dihydroxy-20 ( R )-(3 '(S) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-three Copregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 29 ( S ));

-1 ( S ), 3 ( R ) -dihydroxy-20 ( R )-(3 '(S) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-seco Pregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 30 ( R ));

-1 ( S ), 3 ( R ) -dihydroxy-20 ( R )-(3 '(S) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-three Copregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 30 ( S ));

-1 ( S ), 3 ( R ) -bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxy-prop-1' ( E ) -enyl)- 9,10-Secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (Compound 31 ( R ));

-1 ( S ), 3 ( R ) -bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '-( S ) -hydroxyprop-1' ( E ) -enyl)- 9,10-Secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (Compound 31 ( S ));

-1 ( S ), 3 ( R ) -bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxy-prop-1' ( E ) -enyl)- 9,10-Secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 32 ( R ));

-1 ( S ), 3 ( R ) -bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -9 , 10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 32 ( S ));

-1 ( S ), 3 ( R ) -bis ( tert- butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxyprop-1' ( E )- Enyl) -9,10-secopregna-5,7 ( E ), 10 (19) -triene SO ₂ addition product (Compound 33 ( R ));

-1 ( S ), 3 ( R ) -bis ( tert- butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E )- Enyl) -9,10-secopregna-5,7 ( E ), 10 (19) -triene SO ₂ addition product (Compound 33 ( S ));

-3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( R ) -hydroxy-4'-methylpent-1' ( E ) -enyl), 9,10- SO ₂ addition product of cecopregna-5,7 ( E ), 10 (19) -triene (Compound 34 ( R ));

-3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( S ) -hydroxy-4'-methylpent-1' ( E ) -enyl), 9,10- SO ₂ addition product of Secopreg-na-5,7 ( E ), 10 (19) -triene (Compound 34 ( S ));

-1 ( S ), 3 ( R ) -bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '-( R ) -hydroxyprop-1' ( E ) -enyl)- SO ₂ addition product of 9,10-secopregna-5,7 ( E ), 10 (19) -triene (Compound 35 ( R ));

-1 ( S ), 3 ( R ) -bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -9 SO ₂ addition product of, 10-seco-pregna-5,7 ( E ), 10 (19) -triene (Compound 35 ( S ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-phenyl-4'-oxobut-1 '( E ) -enyl) -9,10 Saecopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 36);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-cyclopropyl-4'-oxobut-1 '( E ) -enyl) -9, 10-Secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 37);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-oxopent-1 '( E ) -enyl) -9,10-seco-pregna -5 ( E ), 7 ( E ), 10 (19) -triene (compound 38);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-hydroxy-4'-methylpent-1 '( E ) -enyl) -9, 10-Secopregna-5 ( E ) -7 ( E ), 10 (19) -triene (Compound 39);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-hydroxy-5'-methylhex-3'-yne-1 '( E )- Enyl) -9,10-secopregna-5,7 ( E ), 10 (19) -triene (compound 40);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( R ) -hydroxy-5'-methylhep-3'-yne-1' ( E ) -enyl) -9,10-secopregna-5,7 ( E ), 10 (19) -triene (Compound 41 ( R ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( S ) -hydroxy-5'-methylhep-3'-yne-1' ( E ) -enyl) -9,10-secopregna-5,7 ( E ), 10 (19) -triene (Compound 41 ( S ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-ethyl-5'-hydroxyhep-3'-yne-1 '( E )- Enyl) -9,10-secopregna-5 (E), 7 (E), 10 (19) -triene (Compound 42);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( R ) -hydroxyhex-3'-yne-1' ( E ) -enyl) -9,10-secopregna-5,7 ( E ), 10 (19) -triene (Compound 43 ( R ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( S ) -hydroxyhex-3'-yn-1' ( E ) -enyl) -9,10-secopregna-5,7 (E), 10 (19) -triene (Compound 43 ( S ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-ethyl-5'-hydroxyhep-3'-yne-1 '( E )- Enyl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 44);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-ethyl-5'-hydroxyhep-3'-yne-1 '( E )- Enyl) -9,10-secopregna-5,7 ( E ), 10 (19) -triene SO ₂ addition product (compound 45);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-oxo-penta-1 '( E ), 3' ( E ) -diene-1 ' -Yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 46);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-methoxycarbonylbuta-1 '( E ), 3' ( E ) -diene- 1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 47);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-hydroxypenta-1 '( E ), 3' ( E ) -diene-1 ' -Yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 48);

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( R ) -hydroxyhexa-1' ( E ), 3 '( E ) -diene -1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 49 ( R ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( S ) -hydroxyhexa-1' ( E ), 3 '( E ) -diene -1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 49 ( S ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( R ) -hydroxyhepta-1' ( E ), 3 '( E ) -diene -1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 50 ( R ));

-1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( S ) -hydroxyhepta-1' ( E ), 3 '( E ) -diene -1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 50 ( S ));

-1 ( S ), 3 ( R ) -bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-hydroxy-5'-methylhexa-1 '( E ),-3' ( E ) -diene-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 51);

-1 ( S ), 3 ( R ) -bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( R ) -hydroxy-5'-methylhepta-1' ( E ), 3 '( E ) -diene-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 52 ( R ));

-1 ( S ), 3 ( R ) -bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( S ) -hydroxy-5'-methylhepta-1' ( E ), 3 '( E ) -diene-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 52 ( S ));

-1 ( S ), 3 ( R ) -bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-ethyl-5'-hydroxyhepta-1 '( E ), 3' ( E ) -Diene-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 53);

-1 ( S ), 3 ( R ) -bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-hydroxy-5'-methylhexa-1 '( E ),-3' ( E ) -diene-1'-yl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (Compound 54); And

-1 ( S ), 3 ( R ) -bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-ethyl-5'-hydroxyhepta-1 '( E ), 3' ( E ) -Diene-1'-yl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 55).

Preferred vitamin D derivatives of formula (I) include, for example, C24 hydroxyl groups such as secalciferol, calcipotriol, tacalcitol and the like, for example calcitriol and the like. C25 hydroxy groups, or those having a C26 hydroxy group such as, for example, EB-1089.

More specifically, preferred vitamin (I) vitamin derivatives have unsaturated (eg, trans double bonds or triple bonds) between C22-C23 carbons, which can be hydroxylated at the 24, 25 or 26 positions; This is followed by chains which may or may contain other unsaturations.

Vitamin D derivatives of formula (I) are represented by the following formula (II)

(II)

It can be obtained from the alkenyl monohalo derivative of,

In the formula,

A has the same meaning as described above; And

X is a halogen atom selected from chlorine, bromine and iodine.

In one embodiment, the compound of formula (II) used is a compound wherein A is selected from (A1), (A2) and (A3), and X is selected from chlorine, bromine and iodine, preferably iodine.

In another embodiment, the compound of formula (II) used is a compound wherein A is (A1) and W is SO ₂ .

In another embodiment, the compounds of formula (II) used are those in which Z and Z 'are, independently of one another, hydroxy groups protected with hydroxy groups or hydroxyl protecting groups, for example silyl or acyl derivatives, and R' ₁ , R ' ₂ and R' ₃ are compounds which are hydrogen at the same time.

In another embodiment, Compound A of Formula (II) used is selected from (A1), (A2) and (A3); X is selected from chlorine, bromine and iodine, preferably iodine; Z and Z ', independently of one another, are hydroxy groups protected with a hydroxy group or a hydroxyl protecting group, for example silyl or acyl derivatives, and R' ₁ , R ' ₂ and R' ₃ are simultaneously hydrogen.

In one embodiment, the aforementioned compound of formula (II) is selected from the group consisting of compounds of formula (IIA1), (IIA2) and (IIA3):

Compound IIA1

(IIA1a) (IIA1b)

Compound IIA2

(IIA2a) (IIA2b)

Compound IIA3

(IIA3a) (IIA3a)

In the formula,

STBDM or MDBTS is ter--butyldimethylsilyl group; And

Ac is an acetyl group.

The compound of formula (II) used is a compound in which the C22-C23 double bond has a trans stereochemistry.

The compound of formula (II) is prepared by the process comprising the steps of: prior to forming various types of organometallic compounds by substituting halogens present in the compound of formula (I) with a selectively complexed metal Can be used to obtain the compound. Organometallic intermediates synthesize vitamin D derivatives of formula (I), preferably having an unsaturated (eg trans double bond or triple bond) between C22-C23 carbons, followed by positions 24, 25 or 26 It can be used to form new CC bonds in the synthesis of compounds of formula (I), followed by chains which are hydroxylated to and / or contain other unsaturations. The unsaturated compound can then be reduced to a saturated compound after first protecting the triene system.

In more detail, the present invention provides the following steps:

(i) alkenylmonohalo derivatives of formula (II)

In formula (A), M is an alkali metal, and

R ₈ and R ₉ are, independently from each other, hydrogen; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyl silyl; Or C ₃ -C ₆ cycloalkyl

Formula

M (NR ₈ R ₉ )

Compound of

By reaction in a solvent to obtain the corresponding metal alkynylide, which is followed by

In which R ₅ has the same meaning as described above

R ₅ CON (CH ₃ ) OCH ₃

Compound of, and

In which R ₅ has the same meaning as described above

R ₅ CHO

Reacting with a compound selected from compounds of;

obtaining a compound of formula (I) with m = 0, n = 1 and p = 0;

or,

In formula (B), M is an alkali metal, and

R ₁₀ is C ₁ -C ₆ alkyl

MOR ₁₀

Metal alkoxides and

After reacting in a solvent, reacting, reacting with a silylating agent, and reacting, in which R ₁₀ has the same meaning as described above

LiR ₁₀

By reacting with an alkyl lithium compound of

Obtaining the corresponding lithium alkynide; And after obtaining lithium alkynide

In which R ₅ has the same meaning as described above

R ₅ CON (CH ₃ ) OCH ₃

Compound of, and

In which R ₅ has the same meaning as described above

R ₅ CHO

Reacting with a compound selected from compounds of;

obtaining a compound of formula (I) with m = 0, n = 1 and p = 0;

or

In Formula (C), M, R ₈ and R ₉ have the same meanings as described above.

M (NR ₈ R ₉ )

Compound of

After reacting in the first solvent and reacting, wherein R ₅ and R ₆ have the same meanings as described above

With epoxide

By reaction in a second solvent;

obtaining a compound of formula (I) with m = 0, n = 1 and p = 1;

or,

(D) palladium or nickel complexes, and

Wherein M 'is selected from Li, Mg, Zn, Al, Zr, B and Sn;

T is halogen or C ₁ -C ₅ alkyl;

"O" is 0 or 1, which is 0 when M 'is a monovalent metal; And

p, R ₃ , R ₄ , R ₅ and R ₆ have the same meanings as described above

(T) _o M '(CR ₃ R ₄ ) _p CHR ₅ R ₆

The organometallic compound of is reacted in a solvent;

obtaining a compound of formula (I) with m = 1, n = 0 and p = 1-6;

or,

(E) in the formula

M ″ is selected from alkali metals, alkaline earth metals, Zn, Cu and Ti;

L 'is halogen, C ₁ -C ₅ alkyl, triphenylphosphine, cyanide or sulfosyanide; And

"q" is an integer selected from 0, 1, 2, 3, 4, 5 and 6

M "(L) q

React with a compound of

Wherein E is a chemical formula having the same meaning as described above

Is a residue of;

v is an integer comprising between 1 and the valence of the metal M "; and

M ", L 'and q have the same meaning as described above,

"v" + "q" is the following formula provided that it matches the valence of M and / or the coordination number of M "

(E) vM "(L) q;

To obtain a compound of

And after the obtained compound, wherein R ₅ and R ₆ have the same meaning as described above

R ₅ COR ₆

By reaction with a compound of;

obtaining a compound of formula (I) with m = 1, n = 0 and p = 0;

or,

(F) in the solvent, in the presence of nickel and / or palladium salts, chromium compounds, and

Wherein R ₅ and R ₆ have the same meanings as described above

R ₅ COR ₆

By reaction with a compound of;

obtaining a compound of formula (I) with m = 1, n = 0 and p = 0;

or,

(G) In a solvent, in the presence of a base, the palladium compound and R ₅ in the formula, except for hydrogen, have the same meanings as described above except for hydrogen

CH ₃ COR ₅

By reaction with a ketone of;

obtaining a compound of formula (I) with m = 1, n = 0 and p = 1;

or

(H) In a solvent, in the presence of a base and optionally complexed copper salt (I), optionally in the presence of a phase transfer catalyst, the palladium compound and wherein R ₅ and R ₆ have the following meanings as defined above Chemical formula

CH≡CC (OH) R ₅ R ₆

React with propargyl alcohol of;

obtaining a compound of formula (I) with m = 1, n = 1 and p = 0;

or

(I) In a solvent, in the presence of a base, optionally in the presence of a phase transfer catalyst, the palladium compound and wherein R ₁ and R ₅ have the same meanings as defined above

R ₁ -CH = CH-COR ₅

By reaction with a compound of;

obtaining a compound of formula (I) with m = 2, n = 0 and p = 0;

or,

(J) In the solvent, in the presence of a base and a silver salt, the palladium compound and wherein R ₁ , R ₅ and R ₆ have the same meanings as described above

R ₁ -CH = C (OH) R ₅ R ₆

By reaction with a compound of;

obtaining a compound of formula (I) with m = 2, n = 0 and p = 0; And, if desired,

(ii) converting a compound of formula (I) to another compound of formula (I); providing a method for synthesizing a vitamin D derivative of formula (I) as defined above from a compound of formula (II).

In one embodiment, the following alternative is alternative (A),

The compound of formula (II) is selected from a compound of formula IIA2 and a compound of formula IIA3;

The compound of formula M (NR ₈ R ₉ ) is selected from the group consisting of lithium-diisopropylamide, lithium-dicyclohexylamide, lithium amide, sodium bis (trimethylsilyl) amide and sodium amide;

The solvent is an organic solvent selected from ethers, hydrocarbons and mixtures thereof, preferably tetrahydrofuran (THF);

- formula R ₅ CON (CH ₃₎ OCH ₃ of the amide is 2-methyl-propanoic acid N, N-Methoxymethyl-hydroxylamine amide and cyclopropanecarboxylic acid in N, N - methoxymethyl - it is selected from hydroxyl amide ; And

The compound of formula R ₅ CHO is selected from 2-methylpropanal and cyclopropanecarboxaldehyde.

In another embodiment, the alternative that follows is Alternative (B),

The compound of formula (II) is selected from a compound of formula IIA2 and a compound of formula IIA3;

The metal alkoxide of the formula MOR ₁₀ is selected from the group consisting of sodium t -butoxide, potassium t -butoxide, sodium t -pentoxide and lithium ethoxide;

The solvent is a polar aprotic organic solvent selected from DMSO, DMF, DMPU, HMPT and mixtures thereof;

The silylating agent is of the formula

ClSi (R ₁₁ ) (R ₁₂ ) (R ₁₃ )

As a compound of

R ₁₁ , R ₁₂ and R ₁₃ are each independently hydrogen; C ₁ -C ₈ alkyl; C ₃ -C ₆ cycloalkyl; Or C ₆ -C ₁₄ aryl; Preferably t -butyldimethylsilyl chloride;

The alkyl lithium compound of formula LiR ₁₀ is selected from the group consisting of n -butyl lithium and ethyl lithium;

- formula R ₅ CON (CH ₃₎ OCH _3, the compound 2-methyl-propanoic acid N, N-Methoxymethyl-hydroxylamine amide and cyclopropanecarboxylic acid in N, N - methoxymethyl - is selected from hydroxyl amide ; And

The compound of formula R ₅ CHO is selected from 2-methylpropanal and cyclopropanecarboxaldehyde.

In another embodiment, the alternative that follows is Alternative (C),

The compound of formula (II) is selected from a compound of formula IIA2 and a compound of formula IIA3;

The compound of formula M (NR ₈ R ₉ ) is selected from the group consisting of lithium-diisopropylamide, lithium-dicyclohexylamide, lithium amide, sodium bis (trimethylsilyl) amide and sodium amide;

The first solvent is ether, preferably THF;

The epoxide is iso -butylene oxide; And

The second solvent is a polar aprotic organic solvent, preferably DMPU.

In another embodiment, the alternative that follows is Alternative (D),

The compound of formula (II) is selected from a compound of formula IIA2 and a compound of formula IIA3;

Palladium or nickel complexes include dichloro (1,1'-bis (diphenylphosphino) ferrocene) palladium, tetrakis (triphenylphosphine) palladium and dichloro (1,1'-bis (diphenylphosphino) ferrocene) A compound selected from the group consisting of nickel;

The solvent is an aprotic organic solvent selected from the group consisting of benzene, toluene, tetrahydrofuran, hexane and mixtures thereof; And

Organometallic compounds of the formula (T) _o M '(CR ₃ R ₄ ) _p CHR ₅ R ₆ are selected from diethylzinc and isobutyl magnesium bromine.

In another embodiment, the alternative that follows is Alternative (E),

The compound of formula (II) is selected from a compound of formula IIA2 and a compound of formula IIA3;

The compound of formula M ″ (L) q is selected from lithium, sodium, potassium, n -butyl lithium, sec -butyl lithium and t -butyl lithium;

The solvent is an organic solvent selected from ethers, hydrocarbons, and mixtures thereof, preferably ethyl ethers; And

The compound of formula R ₅ COR ₆ is selected from 2-methylpropanal, cyclopropanecarboxaldehyde, t -butanecarboxaldehyde and cyclohexanecarboxaldehyde.

In another embodiment, the alternative that follows is Alternative (F),

The compound of formula (II) is selected from a compound of formula IIA1, a compound of formula IIA2 and a compound of formula IIA3,

The chromium derivative is selected from chromium halides, chromocene and di-chromosene;

The nickel salt is selected from nickel halides and nickel acetylacetonates;

The palladium salt is selected from palladium halides and palladium acetylacetonate;

The solvent is a polar aprotic organic solvent selected from DMSO, DMF, DMPU, HMPT, DME and mixtures thereof; And

The compound of formula R ₅ COR ₆ is selected from 2-methylpropanal, cyclopropanecarboxaldehyde, t -butanecarboxaldehyde and cyclohexanecarboxaldehyde.

In another embodiment, the alternative that follows is Alternative (G),

The compound of formula (II) is selected from a compound of formula IIA2 and a compound of formula IIA3;

Palladium compounds include tri- t -butylphosphine, tricyclohexylphosphine, 1,1'-bis (di- t -butylphosphine) ferrocene, diphenylphosphino-2- (di- t -butylphosphine Selective from palladium acetate or chloride complexed with phosphine ligands selected from ethyl ferrocene, triphenylphosphine, ditriphenylphosphine, tetrakis (triphenylphosphine) and tris (dibenzylidenoacetone) dipalladium Palladium salts, or palladium complexes complexed with;

The base is (i) a metal alkoxide of formula MOR ₁₀ wherein M is an alkali metal and R ₁₀ is C ₁ -C ₆ alkyl; (ii) R _14, R ₁₅ and R ₁₆ are, independently, hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl of the formula N (R ₁₄₎ (R ₁₅ each Amines of (R ₁₆ ); (iii) a 6 membered heterocyclic base wherein at least 1 is nitrogen; And (iv) an inorganic base selected from alkali metal carbonates and alkali metal hydroxides, preferably sodium t -butoxide;

The solvent is a polar organic solvent selected from THF, DMF, benzene, dioxane, acetonitrile and mixtures thereof; And

The ketone of the formula CH ₃ COR ₅ is selected from acetophenone, methyl-cyclopropylketone and propanone.

In another embodiment, the alternative that follows is Alternative (H),

The compound of formula (II) is selected from a compound of formula IIA1, a compound of formula IIA2 and a compound of formula IIA3;

Palladium compounds include tri- t -butylphosphine, tricyclohexylphosphine, 1,1'-bis (di- t -butylphosphine) ferrocene, diphenylphosphino-2- (di- t -butylphosphine Optionally complexed selected from palladium acetate or chloride complexed with phosphine ligands selected from ethyl ferrocene, triphenylphosphine, ditriphenylphosphine, tetrakis (triphenylphosphine) and tris (dibenzylideneacetone) dipalladium Palladium salts, or palladium complexes;

The base is (i) a metal alkoxide of formula MOR ₁₀ wherein M is an alkali metal and R ₁₀ is C ₁ -C ₆ alkyl; (ii) R _14, R ₁₅ and R ₁₆ are, independently, hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl of the formula N (R ₁₄₎ (R ₁₅ each Amines of (R ₁₆ ); (iii) a 6 membered heterocyclic base wherein at least 1 is nitrogen; And (iv) an inorganic base selected from alkali metal carbonates and alkali metal hydroxides, preferably sodium t -butoxide;

The phase transfer catalyst is an alkyl ammonium halide, preferably tetrabutylammonium chloride;

The optionally complexed copper salt (I) is selected from CuBr, CuI optionally complexed with a phosphine ligand, preferably triphenylphosphine;

The solvent is selected from said bases and aromatic hydrocarbons, preferably from benzene or toluene; And

Propargyl alcohol is selected from 3-methyl-1-butyn-3-ol, 3-methyl-1-pentin-3-ol, 3-ethyl-1-pentin-3-ol and 1-butyn-3-ol do.

In another embodiment, the alternative that follows is Alternative (I),

The compound of formula (II) is selected from a compound of formula IIA1, a compound of formula IIA2 and a compound of formula IIA3;

Palladium compounds include tri- t -butylphosphine, tricyclohexylphosphine, 1,1'-bis (di- t -butylphosphine) ferrocene, diphenylphosphino-2- (di- t -butylphosphine Optional selected from palladium acetate or chloride complexed with phosphine ligands selected from ethyl ferrocene, triphenylphosphine, ditriphenylphosphine, tetrakis (triphenylphosphine) and tris (dibenzylidene-acetone) dipalladium Palladium salts, or palladium complexes complexed with; Preferably palladium acetate optionally complexed with triphenylphosphine or tri- t -butylphosphine;

The base is (i) a metal alkoxide of formula MOR ₁₀ wherein M is an alkali metal and R ₁₀ is C ₁ -C ₆ alkyl; (ii) R _14, R ₁₅ and R ₁₆ are, independently, hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl of the formula N (R ₁₄₎ (R ₁₅ each Amines of (R ₁₆ ); (iii) a 6 membered heterocyclic base wherein at least 1 is nitrogen, such as, for example, pyridine; And (iv) an inorganic base selected from alkali metal carbonates and alkali metal hydroxides, preferably potassium carbonate;

The phase transfer catalyst is an alkyl ammonium halide, preferably tetrabutylammonium chloride;

The solvent is a polar solvent selected from THF, DMF, dioxane, acetonitrile and mixtures thereof; And

The compound of formula R ₁ -CH = CH-COR ₅ is selected from methyl acrylate, ethyl acrylate, acrolein and vinyl methyl ketone.

In another embodiment, the alternative thereof is as alternative (J),

The compound of formula (II) is selected from a compound of formula IIA1, a compound of formula IIA2 and a compound of formula IIA3;

Palladium compounds include tri- t -butylphosphine, tricyclohexylphosphine, 1,1'-bis (di- t -butylphosphine) ferrocene, diphenylphosphino-2- (di- t -butylphosphine Optional selected from palladium acetate or chloride complexed with phosphine ligands selected from ethyl ferrocene, triphenylphosphine, ditriphenylphosphine, tetrakis (triphenylphosphine) and tris (dibenzylidene-acetone) dipalladium Palladium salts, or palladium complexes complexed with; Preferably palladium acetate optionally complexed with tri- t -butylphosphine;

The silver salt is selected from silver acetate, silver carbonate and silver nitrate;

The solvent is a polar solvent selected from THF, DMF, dioxane, acetonitrile and mixtures thereof, preferably THF; And

Compounds of the formula R ₁ -CH = C (OH) R ₅ R ₆ are 1-butene-3-ol, 1-penten-3-ol, 3-methyl-1-buten-3-ol, 3-methyl- 1-penten-3-ol and 1-pentpro-3-ol.

If desired, the compound of formula (I) obtained is as follows:

(a) treating with SO ₂ in a solvent to form an SO ₂ adduct of the compound of formula (I) wherein A is (A2) or (A3), wherein A is (A1) and W By forming a compound of formula (I) wherein is SO ₂ ;

or,

(b) reducing the compound of formula (I) comprising at least one triple bond (n ≧ 1) and a hydroxyl group (Y = OH) with a triple-bond reducing agent, optionally in the presence of a base, in a solvent, at least By obtaining a compound of formula (I) comprising one double bond and one OH group (Y = OH);

or,

(c) in a solvent with a carbonyl group reducing agent, where D is a compound of formula (I) wherein D is —C (O) R ₅ to obtain a compound of formula (I) wherein Y is OH;

or,

(d) where the compound of formula (I) comprises a group (A2) or (A3), first protected with SO ₂ and then in the solvent, in the presence of a metal catalyst, in the formula "m" ≧ 1 or “n” ≧ 1 or “m” and “n” are all ≧ 1 by hydrogenating a compound of formula (I);

or,

(e) in a solvent, heating in the presence of a base, adduct breakdown of a compound of formula (I) wherein A is (A1) and W is SO ₂ , wherein A is (A2) By obtaining a compound of the general formula (I)

or,

(f) photochemical isomerization of a compound of formula (I), wherein A is (A2) to obtain a compound of formula (I), wherein A is (A3);

or,

(g) reacting with a deprotecting agent, wherein Z and Z 'simultaneously deprotection the compound of formula (I), which is a hydroxyl group protected with a hydroxyl protecting group, wherein Z and Z 'is simultaneously obtained by obtaining a compound of formula (I) which is a hydroxy group

Other preferred compounds of formula (I) may be converted.

In one embodiment, to actually implement alternative (a), one can use a solvent such as an aprotic organic solvent selected from ether, methylene chloride, benzene and mixtures thereof, preferably methylene chloride.

In another embodiment, to actually implement alternative (b), triple-, such as hydrides derived from aluminum selected from Red-Li, LiAlH ₄ , methyl-di- iso - butylaluminum and lithium hydride Bond reducing agents; Bases such as metal alkoxides selected from sodium methoxide, sodium ethoxide and potassium t-butoxide; may be used in a solvent selected from ethers, aromatic hydrocarbons and mixtures thereof, preferably THF.

In another embodiment, to actually implement alternative (c), alkyl lithium, alkyl cerium, and LiAlH ₄ , NaBH ₄ , Redal, Alpine-Borane, Dibal (Diisobutylaluminium, Diisobutylaluminum), DIP-chloride, Ca (BH ₄ ) ₂ , NaBH ₄ / CeCl ₃ , organomagnesium such as methyl lithium and ethyl lithium, for example as selected from metal hydrides or alkyl metals. Carbonyl group reducing agent can be used.

In another embodiment, to actually implement alternative (d), a metal catalyst selected from Pd, Pt and Rh, preferably Pt / C; And a polar solvent selected from methanol, ethanol, ethyl acetate, DMF and mixtures thereof, optionally mixed with an apolar solvent selected from benzene, toluene and mixtures thereof, preferably an ethanol / benzene mixture can be used. have.

In another embodiment, to actually implement alternative (e), a base selected from alkali metal carbonates and alkali metal bicarbonates, preferably sodium bicarbonate, and from methanol, ethanol, isopropanol, butanol, DMF and mixtures thereof It is possible to use selected polar solvents, preferably DMF.

In another embodiment, the photochemical isomerization of a compound of formula (I) wherein A is A2 (alternative (f)) is carried out in a solvent,

- optionally, R _14, R ₁₅ and R ₁₆ are, independently of one another, hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl of the formula N (R ₁₄₎ of the formula ( In the presence of an amine of R ₁₅ ) (R ₁₆ ), with diffuse daylight and I ₂ ;

or,

Optionally with diffused daylight and I ₂ in the presence of a 6 membered heterocyclic base wherein at least 1 is nitrogen;

or,

With phenyl diselenide and tungsten light;

or,

Ultraviolet light in the presence of an aromatic photosensitizer.

Is performed.

Preferably, the aforementioned photochemical isomerization is carried out with UV light, the solvent is toluene and the photosensitizer is anthracene.

In order to actually implement alternative (g), the nature of the hydroxyl protecting group must be taken into account; To explain:

If the hydroxyl protecting group is a silyl group, the deprotecting vaporization is carried out in a solvent, optionally in the presence of a phase transfer catalyst, with a deprotecting agent selected from fluorine and alkoxides;

or

If the hydroxyl protecting group is an acyl group, deprotecting gasification is carried out in a solvent, optionally in the presence of a phase transfer catalyst, with a deprotecting agent such as an alkoxide or inorganic base.

In one embodiment, the hydroxyl protecting group is a silyl group and the deprotecting agent is tetrabutylammonium fluorine in tetrahydrofuran or, alternatively, potassium t -butoxide in DMSO. In another embodiment, the hydroxyl protecting group is an acyl group, the deprotecting agent is sodium or potassium hydroxide, and the solvent is ethanol.

Compounds of formula (II) are disclosed in co-application (co-application) patent application No. 200302806, wherein A, with respect to the compound of formula (I), has the following meaning Chemical formula

Compound of

Haloform selected from chloroform, bromoform and iodineform,

In an organic solvent, it can be obtained by reacting in the presence of a salt or divalent chromium complex (Cr ²⁺ ).

Disclosed below are specific examples of obtaining a vitamin D derivative of formula (I) by a compound of formula (II) by the method presented by the present invention, according to the nomenclature of the examples and methods used in Tables 1 and 2 . As can be seen here, the compound of formula (II) is a reagent generally named M (L) q in this specification, and various kinds of organometallics are substituted by metals of halogen (X) present in the compound of formula (I). The compounds are formed in advance and used in the synthesis of compounds of formula (I), in which M is for example an alkali metal (Li, Na, K, etc.), a Group 6 metal (Cr, etc.) in the periodic table of the elements. , Group 10 metals (Ni, Pd, etc.) in the periodic table of the elements; Metals such as and the like; L is a ligand that forms a covalent or complex ionic bond, such as, for example, alkoxides, halides, alkylides, alkylcarboxylates, amides, phosphine derivatives, and the like; And q is an integer comprising between 0 and 6, which matches the valence and / or coordination number of M.

1. Preparation of a compound of formula (I) wherein m = 0, n = 1, p = 0 or 1 and Y = OH

Section A: p = 0

Method 1A / 1

These alkyne derivatives are formulated according to the method disclosed by Calverley ( Bioorg. Med. Chem. Letter ; 1993) or as disclosed herein in which MDA, R ₈ and R ₉ have the same meaning as described above. By reaction with the M (L) q-type compound of formula M (NR ₈ R ₉ ) or in formulas such as potassium t -butoxide ( t -BuOK) in other DMSO, M and R ₁₀ are as defined above. By reaction with a compound of the formula MOR ₁₀ with meaning, it can be prepared from monohalogenalkenes (IIA2) and (IIA3). If the reaction is carried out with lithium-diisopropylamide (LDA), the intermediate product obtained is a lithium salt (lithium alkynide) (step 1a), whereas if it is carried out with t- BuOK / DMSO, desilylated Alkynes are formed (step 1b), for example, wherein R ₁₁ , R ₁₂ and R ₁₃ are the same as the compounds of formula ClSi (R ₁₁ ) (R ₁₂ ) (R ₁₃ ) having the same meaning as described above, Wherein R ₁₀ is silylated with a silylating agent treated with a LiR ₁₀ -type reagent such as n- BuLi having the same meaning as described above, then the desilylated alkyl becomes lithium alkynide (step 2b) . The obtained lithium alkynide can be reacted with the corresponding amide of N , N -methoxymethyl-hydroxylamine (step 2a), and the resulting propargyl ketone is DIP-chloride, R ₆ Li, NaBH ₄ , Reduced with a reducing agent such as REDAL, alpin-borane and the like (step 3a); Alternatively, the lithium salt can be reacted with an aldehyde of formula R ₅ CHO (step 3b) in which R ₅ has the same meaning as described above.

Any other compound of formula M (NR ₈ R ₉ ), such as lithium dicyclohexylamide, lithium amide, sodium bis (trimethylsilyl) amide, sodium amide, and the like, can also be used in place of LDA. The reaction can be carried out in a solvent such as ether, hydrocarbon, or a mixture of both and at a temperature comprising -100 ° C to + 50 ° C, preferably at a temperature of -80 ° C to -70 ° C.

Similarly, another alkoxide of formula MOR ₁₀ may be used in place of t- BuOK, for example sodium t -butoxide, sodium t -pentoxide, lithium ethoxide and the like, and dimethyl sulfoxide (DMSO), dimethylformamide (DMF), DMPU, HMPT and the like can be used in polar aprotic organic solvents, of which DMSO is a preferred solvent. The reaction can be carried out at a temperature comprising -10 ° C to + 120 ° C, preferably at a temperature of 50 ° C to 60 ° C.

Step 2a, treated with n- BuLi (n-butyl lithium), can also be performed with another alkyl lithium of the formula LiR ₁₀ , for example ethyl lithium or the like, to obtain the corresponding alkynide.

Preferred compounds of the formula C ₅ CHO are aldehyde 2-methylpropanal and cyclopropanecarboxaldehyde.

Preferred amides of formula _{R 5 CON (CH 3) OCH} 3 are in the 2-methyl-propanoic acid N, N - is the hydroxyl amide-Methoxymethyl-hydroxylamine amide and cyclopropanecarboxylic acid in N, N - methoxymethyl .

The resulting acetone can be reduced with propargyl ketone reducing agents such as NaBH ₄ , Alpin-Borrain, Dip-chloride, Redal, etc., preferably reduced to Alpin-Borane or Dip-chloride, whereby C-24 mirror image and the S / R ratio of the borane is 9/1, (+) - isomer is to be obtained rich alcohol (Biorg Med Chem Letter, according to the 1993 S -... Alpine S / R ratio with respect to chloride Dip- Is 2.5 / 1 and the 1/1 ratio is used if the aldehyde route is used (step 3b)).

Section B: p = 1

Method 1B / 1

Compounds of this type are obtained from compounds of formula (II), for example compounds of formula (IIA2a) or compounds of (IIA3a), according to the following schemes, wherein M, R ₈ and R ₉ are The following formula is reacted with an M (L) q-type compound of formula M (NR ₈ R ₉ ), defined as follows, in which R ₅ and R ₆ have the same meanings as described above in the presence of a polar aprotic solvent.

Obtained by subsequent reaction with an epoxide of;

Same amides as the amides disclosed in connection with Method 1A / 1, LDA, lithium-dicyclohexylamide, lithium amide, sodium bis (trimethylsilyl) amide, sodium amide and the like, preferably lithiated derivartive, more preferred Preferably an amide such as LDA can be used as the reagent of formula M (NR ₈ R ₉ ).

Among the epoxides, iso -butylene oxide is preferred.

Ethers, hydrocarbons or mixtures of both can be used as the solvent of step a), preferably THF.

As solvent of step b) (second solvent), polar aprotic solvents such as DMSO, DMPU, DMI, HMPT, TMU and the like can be added to the first solvent (step a)), preferably DMPU.

The reaction can be carried out at a temperature comprising -100 ° C to + 50 ° C, preferably at a temperature of -15 ° C to + 5 ° C.

If the epoxide is chiral, chiral alcohol will be obtained while retaining the optical purity of the epoxide.

2. Preparation of Compounds of Formula (I) wherein m = 1, n = 0, p = 0-6 and Y = H

Method 2/1

Compounds of this type are reacted with a palladium or nickel complex [M (L) q-type reagent] in a solvent according to the following scheme, wherein T, M 'R ₃ , R ₄ , R ₅ , R ₆ , o and p are reacted with organometallic compounds of formula (T) _o M' (CR ₃ R ₄ ) _p CHR ₅ R ₆ having the same meaning as described above. Can be manufactured:

Phosphine derivatives such as dichloro (1,1'-bis (diphenylphosphino) ferrocene) palladium, tetrakis (triphenylphosphine) palladium, dichloro (1,1'-bis (diphenylphosphino) ferrocene) nickel and the like Is a usable palladium or nickel complex; Preferably it is tetrakis (triphenylphosphine) palladium.

As the organometallic compound, M 'is preferably Mg or Zn, of which diethylzinc and iso -butyl magnesium bromine are preferred.

The reaction is carried out in an aprotic solvent or mixtures thereof, preferably benzene, toluene, THF and hexane, or mixtures thereof, and at temperatures comprising -30 ° C to + 60 ° C, preferably 20 ° C to 30 ° C. It can be performed in.

3. Preparation of compounds where m = 1, n = 0, p = 0 and Y = OH

Method 3/1

Compounds of this type are, for example, monohalogenalkenes of formula (II), such as compounds of formula (IIA2a) or compounds of formula (IIA3a), wherein M ″, L ′ and q are compounds of general formula (I) Reacting with an M (L) q-type reagent of the general formula M ″ (L ′) q having the same meanings as described above with respect to (E) of the process for preparing the same, and subsequently reacting with an aldehyde or ketone, It can be prepared according to the scheme of:

Intermediate organometallic compounds of formula (VIa) can be prepared by different routes, for example:

a) by direct insertion of metals, in particular alkali metals, alkaline earth metals or Zn, preferably lithium;

b) by reacting with an organometal, in particular with an organometal that is a lithium derivative or magnesium derivative, for example n- BuLi, sec - BuLi, t- BuLi, CH ₃ BrMg and the like;

c) by the exchange of compounds of section b) (particularly when the metal is a transition metal), for example by the exchange of lithium derivative metals with ZnI ₂ , CuBr, CeI ₃ and the like.

Preferably, the intermediate organometallic compound of formula (VIa) is obtained by reaction with an organometallic compound, preferably by reaction with t -BuLi.

The reaction is carried out at a temperature comprising -100 ° C to + 25 ° C, preferably at a temperature between -70 ° C and -80 ° C, and in an organic solvent selected from ethers, hydrocarbons and mixtures thereof, preferably ethyl ethers. do.

Among the carbonyl compounds of the formula R ₅ COR ₆ , aldehydes are preferred, for example 2-methylpropanal, cyclopropanecarbaldehyde, trimethylacetaldehyde or cyclohexane-carboxaldehyde.

If R ₅ and R ₆ are different, the alcohol obtained is chiral in C-24 with an S / R ratio of 1 and the amount obtained exceeds that obtained by reduction of the corresponding ketone with NaBH ₄ . This increase in S isomers is a possible result without the need to use chiral reagents or catalysts.

Method 3/2

These compounds can also be obtained by reducing the corresponding alkynes (m = 0, n = 1, p = 0) with suitable reducing agents, for example metal hydrides.

Alkynes can be prepared according to the methods disclosed in section A of heading 1: Preparation of compounds of formula (I) wherein m = 0, n = 1, p = 0 and Y = OH.

Triple bond and are optionally, for example, sodium methoxide, sodium ethoxide, potassium t-under alkoxide presence of a base such as t-butoxide, metal hydride, preferably Redal, LiAlH _4, lithium and methyl-di-iso-butyl Hydrogenated aluminum derivatives such as aluminum hydride and the like can be used to reduce the corresponding trans -alkenes. Reduction of the triple bond is preferably carried out with Redal or with LiAlH ₄ and CH ₃ ONa.

The reaction is carried out in an organic solvent selected from, for example, ethers such as ethyl ether, dioxane, THF and the like, hydrocarbons such as benzene, toluene and the like, and mixtures thereof, preferably THF, dioxane or mixtures thereof. Can be.

The reaction can be carried out at a temperature including the boiling point of the solvent from 0 ° C, preferably at a temperature including 60 ° C to 70 ° C.

When R ₅ and R ₆ are different, inde-obtained alcohol is chiral, S / R ratio of the C-24 is the same as the S / R ratio of propargyl alcohol starting material (if propargyl alcohol is (S) - If prepared by reduction of the corresponding ketone with alpin-borane, the S / R ratio will reach 9/1).

Method 3/3

Another method for preparing these compounds is to convert a compound of formula (II), for example a compound of formula (IIA1), (IIA2) or (IIA3), into a chromium compound [M (L) q reagent according to the following scheme. And in the presence of a catalytic amount of Ni ²⁺ or Pd ²⁺ salt, the reaction with a carbonyl compound:

Among the preferred chromium compounds are those compounds in which chromium is present as divalent chromium (Cr ⁺² ), for example CrCl ₂ , chromocene, dichloro-chromocene and the like, preferably CrCl ₂ ; Alternatively, it is possible to use a catalytic amount and regenerate with Mn, or use CrCl ₂ obtained by in situ reduction of CrCl ₃ with Mn or tetrakis (dimethylamino) ethylene.

Preferred Ni ²⁺ or Pd ²⁺ salts are selected from halides, preferably chlorides, and acetylacetonate-type organic salts.

The reaction is carried out in polar aprotic organic solvents such as DMSO, DMF, DMPU, HMPT, DME and the like, preferably in DMSO or DMF.

The reaction is carried out at a temperature comprising -30 ° C to + 70 ° C, preferably between 20 ° C and 30 ° C.

Preferred carbonyl compounds are aldehydes, among which cyclopropanecarboxaldehyde and 2-methyl-propanealdehyde.

Preferred compounds of formula (II) are compounds of formula (IIA1).

As in Method 3/1, if the alcohol obtained is chiral (R ₅ ≠ R ₆ ), then the S / R isomer ratio at C-24 is also 1/1.

Method 3/4

The preparation of these compounds is also preferred from aldehydes of formula (III) or 4 below, in which Z, Z 'and W have the same meanings as described above in connection with compounds of formula (I) Preferably in the presence of a divalent chromium complex (Cr ²⁺ ) or salt from an aldehyde of formula (IV) with an haloform selected from chloroform, bromoform and iodineform in an organic solvent to separate the halogenated derivatives. And may be performed by a one-pot method.

(IV) (III)

Preferred starting materials, aldehydes, are SO ₂ adducts [W is a compound of formula (IV) wherein SO ₂ is].

Preferred haloform is iodineform (I ₃ CH).

Virtually any divalent chromium salt (Cr ²⁺ ) can be used; However, in one embodiment, the aforementioned divalent chromium salt is reacted in situ with Cl ₂ Cr, chromosene, dichloro-chromosene or, for example, Mn (Mn / Et ₃ SiCl) or tetrakis (dimethylamino) ethylene. Selected from reduced Cl ₃ Cr, preferably Cl ₂ Cr. The salt can be used in catalytic amounts and can be regenerated with Mn or Mn / Et ₃ SiCl.

The solvent of step a) is a polar aprotic organic solvent, preferably THF. The solvent of step b) is a polar aprotic organic solvent, preferably DMF or DMSO.

The first step of the reaction [step a)] can be carried out at a temperature including -80 ℃ to +60 ℃, preferably at -5 ℃ to +5 ℃. The second step [step b)] may be carried out at a temperature including −30 ° C. to + 60 ° C., preferably at 20 ° C. to 30 ° C.

Preferred carbonyl compounds are 2-methylpropanal and cyclopropanecarboxaldehyde.

Also in this case, if R ₅ ≠ R ₆ , the S and R isomers are formed at a ratio of 1 to 1 in C-24.

Method 3/5

Compounds obtained according to methods 3/3 and 3/4 protected in the form of SO ₂ adducts are heated in a polar solvent such as ethanol, iso- propanol, butanol, DMF, etc., in the presence of a base such as an alkali metal carbonate or bicarbonate. This can be returned to the triene system (adduct breakdown). In one embodiment, the adduct decomposition may be carried out at a temperature of 80 ° C., in the presence of NaHCO ₃ , in DMF or EtOH.

Method 3 of 6

Compounds having a trans- triene system in C-5 obtained according to methods 3/1, 3/2 and 3/5 may optionally be selected from i) wherein R ₁₄ , R ₁₅ and R ₁₆ have the same meaning as described above. An amine of formula N (R ₁₄ ) (R ₁₅ ) (R ₁₆ ), or ii) at least one of which is nitrogen, photochemical isomers with diffuse daylight and I ₂ in the presence of a six-membered heterocyclic base such as pyridine In harmony; Or by treatment with phenyl diselenide and tungsten light in nonpolar organic solvents such as hexane, toluene, benzene, xylene, t-butylmethylether, or aromatic photosensitizers such as anthracene, acetylanthracene, phenazine, acridine, etc. Treatment with ultraviolet light in the presence of an agent can be converted to the corresponding cis homologue at C-5.

Method 3/7

Compounds protected by hydroxides at positions 1 and 3 (Z = Z ′ = hydroxyl protected with a hydroxyl protecting group), prepared according to the process (3/1 to 3/6) described above, wherein R is a silyl radical Optionally, in the presence of a phase transfer catalyst such as crown ether or tetraalkylammonium halide, deprotected with fluorine or alkoxide at a temperature comprising a temperature between 0 ° C. and 65 ° C., Z = Z ′ = The compound of formula (I) which is OH can be obtained. Tetrabutylammonium fluoride is preferably used at temperatures including 0 ° C to 65 ° C.

Method 3/8

Compounds protected by hydroxides at positions 1 and 3 (Z = Z ′ = hydroxyl protected with hydroxyl protecting groups), prepared according to the aforementioned methods (3/1 to 3/6), have a hydroxyl protecting group of acetyl Group, optionally in the presence of a phase transfer catalyst such as crown ether or tetraalkylammonium halide, at a temperature including 0 ° C. to 65 ° C., with an alkoxide or inorganic base, preferably sodium or potassium inorganic base Deprotection may be performed to obtain a compound of formula (I) wherein Z = Z ′ = OH. In one embodiment, the deprotection vaporization in this case may be carried out with EtOH / NaOH or EtOH / KOH at temperatures including 0 ° C. to 65 ° C.

Such hydrolysis can also be carried out in the reaction crude product of Method 3/5 without separation of the de-additioned product.

4.m = 1, n = 0, p = 1 and D = C (O) R ₅  Or D = CR where Y = OH ₅ R ₆ Preparation of Compounds of Formula (I) Y

Method 4/1

A compound of formula (I) wherein D is C (O) R ₅ is a compound of formula (II), such as a compound of formula (IIA2) or a compound of (IIA3), palladium complex or complex palladium salt, according to the following scheme In the presence of a palladium compound [Pd (L) q] and a suitable ligand such as a phosphine-type ligand, by condensation, it can be obtained by reaction with a ketone:

Among the palladium compounds that can be used are optionally tri- tert -butylphosphine, tricyclohexylphosphine, 1,1'bis (di- tert -butylphosphine) ferrocene (D- t- BPF), diphenylphosphino Palladium acetate or palladium chloride, and tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ) complexed with 2- (di- tert -butylphosphino) ethylferrocene (PPF- t- Bu ₂ ) and the like Palladium complexes; Palladium acetate complexed with tri- tert -butylphosphine is preferably used.

The reaction includes (i) a metal alkoxide of formula MOR ₁₀ in which M and R ₁₀ have the same meanings as described above; (ii) R ₁₄ , R ₁₅ and R ₁₆ are amines of the formula N (R ₁₄ ) (R ₁₅ ) (R ₁₆ ) having the same meanings as described above; (iii) a 6 membered heterocyclic base wherein at least one of the atoms is nitrogen; And (iv) an inorganic base selected from alkali metal carbonates and alkali metal hydroxides. The base mentioned above is preferably sodium t -butoxide.

The reactions described above are carried out in polar organic solvents such as THF, dioxane, benzene, DMF, acetonitrile and the like at temperatures between −10 ° C. and the boiling point of the solvent, preferably between 10 ° C. and 30 ° C. , Preferably in THF.

In the ketone of the formula CH ₃ COR ₅ , R ₅ has the same meaning as described above. Acetophenone, methylcyclopropyl ketone and propanone are preferred among the ketones that may be used.

Method 4/2

According to the following reaction scheme, the ketone obtained according to method 4/1 is reduced with an appropriate reducing agent such as alkyl metal or metal hydride, where m = 1, n = 0, p = 1 and D = CR ₅ Obtain a compound of formula (I) wherein R ₆ Y, wherein Y = OH:

Examples of metal hydrides that can be used include LiAlH ₄ , NaBH ₄ , Redal, Alpin-Borrain, Dibal, DIP-chloride, Ca (BH ₄ ) ₂ , NaBH ₄ / CeCl _3, etc., preferably NaBH ₄ to be.

Among the alkyl metals that can be used are alkyl lithium, organomagnesium, alkyl cerium, and the like, preferably alkyl lithium, wherein the alkyl radical is a low molecular weight alkyl radical, for example a C ₁ -C ₆ alkyl radical.

The reaction is carried out in a solvent selected from those compatible with the reducing agent to be used, for example ethers, hydrocarbons or mixtures of such solvents, preferably THF.

The reaction may be carried out at a temperature including -100 ° C to + 20 ° C, preferably at -60 ° C for reaction with alkyl lithium, and 20 ° C to 0 ° C for reaction with metal hydride It may be carried out at ℃.

5.m = 1, n = 1, p = 0, R ₅  And R ₆  Preparation of compounds wherein = alkyl and Y = OH

Method 5/1

Using a palladium compound [Pd (L) q], a base, a copper salt [Cu ⁺ ] and a propargyl alcohol, such as a palladium complex or optionally complexed palladium salt, for example, halogen derivatives (IIA1) It is also possible to introduce hydroxylated alkyne at the α position of a compound of formula (II) such as (IIA2) or (IIA3):

Among the palladium compounds that can be used are optionally tri- tert -butylphosphine, tricyclohexylphosphine, 1,1'bis (di- tert -butylphosphine) ferrocene (D- t- BPF), diphenylphosphino- Palladium chloride or acetate complexed with 2- (di- tert -butylphosphino) ethylferrocene (PPF- t- Bu ₂ ) and the like, and tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ), PdCl Palladium complexes such as ₂ (PPh ₃ ) ₂ , tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ ), and the like. In one embodiment, the palladium compound is selected from PdCl ₂ , PdCl ₂ (PPh ₃ ) ₂ and Pd (PPh ₃ ) ₄ , preferably Pd (PPh ₃ ) ₄ .

The reaction includes (i) a metal alkoxide of formula MOR ₁₀ in which M and R ₁₀ have the same meanings as described above; (ii) R ₁₄ , R ₁₅ and R ₁₆ are amines of the formula N (R ₁₄ ) (R ₁₅ ) (R ₁₆ ) having the same meanings as described above; (iii) a 6 membered heterocyclic base wherein at least one of the atoms is nitrogen; And (iv) an inorganic base selected from alkali metal carbonates and alkali metal hydroxides.

The aforementioned bases are preferably selected from triethylamine, pyridine, NaOH and CO ₃ K ₂ , and more preferably concentrated sodium hydroxide.

The reaction can be increased using a phase transfer catalyst when the base is a base such as a quaternary ammonium halide, for example benzyltriethylammonium chloride, so that the base is dissolved in water.

Alternatively, copper halides (I) complexed with phosphine ligands such as, for example, phosphine ligands, BrCu, ICu, ICu.PPh ₃ and the like, preferably ICu, may be used as copper salts.

As a solvent for the reaction, if the base itself is an organic base, it can be used as a solvent in the reaction, or if the base is dissolved in water (inorganic), hydrocarbons can be used, in which case preferred hydrocarbons are benzene, toluene and the like. It is the same aromatic hydrocarbon.

The reaction may be carried out at a temperature including the boiling point of the solvent from 0 ° C., preferably at the reflux temperature of the organic base, and at a temperature including 20 ° C. to 30 ° C. for the aqueous inorganic base.

Wherein R ₅ and R ₆ are the propargyl alcohols of the formula CH≡CC (OH) R ₅ R ₆ having the same meaning as described above, and 3-methyl-1-butyn-3-ol, 3-methyl-1 -Pentyn-3-ol, 3-ethyl-1-pentin-3-ol and 1-butyn-3-ol.

If R ₅ ≠ R ₆ , when racemic propargyl alcohol is used as the starting material, a one-to-one S / R isomeric mixture is obtained at C-26.

If propargyl alcohol is optically pure in either of the two enantiomers, only S or only the final product will be obtained.

6. Preparation of compounds of formula (I) wherein m = 2, n = 0, p = 0.

Section A: R ₅  = H, alkyl, -OR ₇ And D = C (O) R ₅

Method 6A / 1

A compound of this type is a palladium complex or optionally complexed with a compound of formula (II) such as, for example, a compound of formula (IIA1), (IIA2) or (IIA3), in the presence of a base, according to the following scheme Prepared by reaction with an alkene having a carbonyl functional group at the α position, catalyzed by the action of a palladium compound [Pd (L) q] such as a palladium salt:

Among the palladium compounds that can be used are, for example, tri- n -butylphosphine, tri- tert -butylphosphine, triphenylphosphine, tricyclohexylphosphine, 1,1'bis (di- tert -butylphosphine Palladium acetate optionally complexed with phosphine ligands such as ferrocene (D- t- BPF), diphenylphosphino-2- (di- tert -butylphosphino) ethylferrocene (PPF- t- Bu2), and tris Palladium complexes such as (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ); Palladium acetate complexed with tri- n -butylphosphine or triphenylphosphine is preferred.

The reaction includes (i) a metal alkoxide of formula MOR ₁₀ in which M and R ₁₀ have the same meanings as described above; (ii) R ₁₄ , R ₁₅ and R ₁₆ are amines of the formula N (R ₁₄ ) (R ₁₅ ) (R ₁₆ ) having the same meanings as described above; (iii) a 6 membered heterocyclic base wherein at least one is nitrogen; And (iv) an inorganic base selected from alkali metal carbonates and alkali metal hydroxides. Preferred base is sodium t -butoxide.

The reaction described above is carried out in a polar organic solvent such as THF, dioxane, benzene, DMF, acetonitrile and the like, preferably in THF, at temperatures ranging from -10 ° C. to the boiling point of the solvent, preferably 10 It is carried out at a temperature between ℃ and 30 ℃.

The reaction includes (i) a metal alkoxide of formula MOR ₁₀ in which M and R ₁₀ have the same meanings as described above; (ii) R ₁₄ , R ₁₅ and R ₁₆ are amines of the formula N (R ₁₄ ) (R ₁₅ ) (R ₁₆ ) having the same meanings as described above; (iii) a 6 membered heterocyclic base wherein at least one is nitrogen; And (iv) an inorganic base selected from alkali metal carbonates and alkali metal hydroxides. The base mentioned above is preferably selected from triethylamine, Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , KOH, and the like, more preferably K ₂ CO ₃ . If, for example, a phase transfer catalyst such as quaternary ammonium halide such as tetrabutylammonium chloride is used, the yield can be increased.

As the solvent of the reaction, a polar solvent such as water, DMF, dioxane, THF, acetonitrile, or a mixture thereof, preferably a THF / DMF mixture, can be used.

The reaction can be carried out at a temperature including the boiling point of the solvent -10 ° C, preferably between 20 ° C and 30 ° C.

Α, β-unsaturated carbonyl compounds that can be used include methyl or ethyl acrylate, vinylmethylketone and acrolein.

Section B: R5 and R6 = Alkyl and Y = OH

Method 6B / 1

These compounds can be obtained from the compounds of section 6A / 1 described above by converting the carbonyl functional groups in the alcohol by reduction with an appropriate reducing agent such as an alkyl metal or metal hydride type organometallic compound according to the following reaction scheme: have:

Among the alkyl metals that can be used are alkyl lithium, organomagnesium, alkyl cerium and the like, preferably alkyl lithium, wherein the alkyl radical is a low molecular weight alkyl radical such as, for example, a C ₁ -C ₆ alkyl radical.

Examples of metal hydrides that can be used include LiAlH ₄ , NaBH ₄ , Redal, Alpin-Borrain, Dibal, DIP-chloride, Ca (BH ₄ ) ₂ , NaBH ₄ / CeCl _3, etc., preferably NaBH ₄ / CeCl ₃ .

The reaction is carried out in a solvent selected from solvents compatible with the reducing agent used; In one embodiment, the solvents described above comprise one or more polar organic solvents, for example THF or THF / MeOH for the reduction reaction with NaBH ₄ / CeCl ₃ .

The reaction is carried out at a temperature comprising -100 ° C to + 35 ° C, preferably at -60 ° C to -70 ° C for reactions using alkyl lithium and -15 ° C to + 70 ° C for reactions with metal hydrides At 25 ° C.

Method 6B / 2

These compounds also contain compounds of the formula (II) such as, for example, the compounds of the formulas (IIA1), (IIA2) and (IIA3), in the presence of a silver salt in the alkali medium, according to the following scheme palladium compounds such as palladium complexes, or optionally a salt complexed with [Pd (L) q] R 1, wherein while catalyzed by the action of the formula R ₅ and R ₆ of the formula -CH R ₁ have the meanings as described above It can be obtained by reacting with an alkene having hydroxyl functionality at the α position of = C (OH) R ₅ R ₆ :

Among the palladium compounds that can be used are tri- tert -butylphosphine, tricyclohexylphosphine, 1,1'bis (di- tert -butylphosphino) ferrocene (D- t- BPF), diphenylphosphino-2- Palladium acetate or chloride optionally complexed with (di- tert -butylphosphino) ethylferrocene (PPF- t- Bu2) and the like, and palladium such as tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ) There is a complex; Palladium acetate (PdAc ₂ ) complexed with phosphines such as triphenylphosphine or tri- tert -butylphosphine is preferred.

The reaction includes (i) a metal alkoxide of formula MOR ₁₀ in which M and R ₁₀ have the same meanings as described above; (ii) R ₁₄ , R ₁₅ and R ₁₆ are amines of the formula N (R ₁₄ ) (R ₁₅ ) (R ₁₆ ) having the same meanings as described above; (iii) a 6 membered heterocyclic base wherein at least one is nitrogen; And (iv) an inorganic base selected from alkali metal carbonates and alkali metal hydroxides. The base described above is preferably selected from K ₂ CO ₃ , Cs ₂ CO ₃ and Et ₃ N, more preferably Cs ₂ CO ₃ .

Organic salts such as silver acetate or the like, or inorganic salts such as, for example, silver carbonate or nitrate, may be used as silver salts; The silver salt used is preferably silver carbonate.

The reaction is carried out in a polar organic solvent such as CH ₃ CN, DMF, THF, dioxane, or mixtures thereof, and preferably in THF.

The reaction can be carried out at a temperature comprising the reflux temperature of the solvent at 0 ° C, preferably at a temperature between 60 ° C and 70 ° C.

In one embodiment, compounds of the formula R ₁ -CH═C (OH) R ₅ R ₆ wherein R ₁ , R ₅ and R ₆ have the same meanings as described above are 1-propen-3-ol, 1 -Butyl-3-ol, 1-penten-3-ol, 3-methyl-1-butene-3-ol and 3-methyl-1-penten-3-ol.

R cases ₅ and R ₆ are different, a chiral allyl alcohol is obtained, S / R isomer ratio of the alcohol is the same as the S / R isomer ratio of the starting material alcohol (If it racemate, the ratio is 1 would).

Method 6B / 3

These compounds can be obtained by the reduction reaction according to the following reaction scheme using a suitable reducing agent for the triple bond of the compound prepared according to Method 5/1.

Triple bond and are optionally, for example, sodium methoxide, sodium ethoxide, potassium t-number of metal in the presence of a base, such as a metal alkoxide, such as butoxide hydride, preferably Redal, LiAlH _4, methyl-di-iso- Aluminum-derived hydrides such as butylaluminum and lithium hydride can be reduced to the corresponding trans alkenes; Preferably, Redal or LiAlH ₄ / MeONa is used.

The reaction can be carried out in an organic solvent selected from ethers such as ethers such as ethyl ether, dioxane, THF and the like, for example hydrocarbons such as aromatic hydrocarbons such as benzene, toluene, xylene and the like, or mixtures thereof, Preferably THF, dioxane or a mixture thereof.

The reaction is carried out at -10 ° C to reflux temperature of the solvent, preferably at 60 ° C to 70 ° C.

If R ₅ and R ₆ are different, a chiral allyl alcohol is obtained in which the isomer ratio is equal to the S / R isomer ratio of the starting alcohol.

7. Preparation of compounds of formula (I) wherein m = 0, n = 0, p> 2

These compounds are prepared from the compounds according to the preceding section, if the triene system is not protected, first by protecting the triene system, for example by catalytic hydrogenation with 5% carbon-supported platinum. It can be prepared by reducing and deprotecting it. The triene system can be protected by forming any SO ₂ adduct by reaction with liquid SO _{2 in} an aprotic organic solvent such as, for example, ether, methylene chloride, benzene, etc. using any suitable conventional means. .

In one embodiment, the reduction may be carried out using H ₂ and transition metals such as Pd, Pt, Rh, etc., preferably using 5% carbon-supported Pt; In polar solvents such as methanol, ethanol, ethyl acetate and the like, or in a mixture of polar solvents with non-polar solvents such as benzene, toluene and the like.

With careful selection of the reducing agent, partial reduction such as, for example, reducing alkyne to alkene ( cis ) may also be performed, or if only one or more double bonds are present, only one of them may be reduced. .

Saturated compounds having carbonyl functional groups can be converted to the corresponding alcohols by reaction with alkyl metals (preferably alkyl lithium) or with metal hydrides according to the methods disclosed in the aforementioned section.

Upon completion of the reduction reaction, SO ₂ is removed by conventional methods such as heating in a polar solvent such as ethanol, isopropanol, butanol, DMF, etc., in the presence of a base such as, for example, an alkali metal carbonate or bicarbonate. In one embodiment, the removal of SO ₂ is carried out in DMF or EtOH and at a temperature of 80 ° C. in the presence of a base, preferably NaHCO ₃ .

As mentioned above, the compounds of formula (I) obtained can be converted to other compounds of formula (I), if desired. Thus, in one embodiment, if desired or if it is deemed necessary to do so, the method described in sections 3/5, 3/6, 3/7 and 3/8 may be obtained in accordance with the method described in the aforementioned section. It can be applied to the compound.

The following examples illustrate the invention but should not be considered in a limiting sense.

In an embodiment:

Nuclear magnetic resonance spectra (NMR, δ) were performed at 300 and 200 MHz in CDCl ₃ solutions using TMS or CHCl ₃ internal standards. The coupling constant J is given in hertz (s = singlet, d = doublet, t = triple, dd = doublet, AB = AB system, m = polyline and bb = broadband or some signal Sum).

Infrared spectra (IR) were performed by KBr pellets, and only the strongest or most characteristic frequencies were given in cm ⁻¹ .

High performance liquid chromatography (HPLC) was performed with a normal phase column: Hypersil, 5 microns and 4.6x100 mm, and dichloroethane or ethyl acetate mixed as hexane and eluent as the eluent, depending on the type of compound to be analyzed. mixture.

Preparative high performance liquid chromatography was performed in PrePac Waters with 10 × 250 mM Microporasil column or 40 × 100 mm silica gel cartridge.

Thin layer chromatography (TLC) was performed on a Merck 60F254 silica gel plate.

Fast preparative chromatography was performed using 60 A and 35-70 micron silica gel at a pressure of 0.75-1.0 atmospheric pressure.

Ultraviolet photochemical reactions were carried out using a TQ 500 Z2 Heraeus lamp.

The solution was dried over anhydrous sodium sulfate containing 5% anhydrous Na ₂ SO ₄ and 5% anhydrous K ₂ CO ₃ ; The solution was filtered and concentrated on a rotary evaporator.

BTEAC means: benzyltributylammonium chloride.

DMAP means: dimethylaminopyridine.

DMI means: 1,3-dimethyl imidazolidinone.

DMPU means: N , N' -dimethylpropylene urea.

EBM means: t -butylmethyl ether.

HMPT means: hexamethylphosphorotriamide.

LDA means: lithium-diisopropylamide.

TBAC means: tetramethylammonium chloride.

TBDMS means: tert -butyldimethylsilyl.

TMU means: tetramethylurea.

All reactions were carried out under a nitrogen atmosphere, which made it essential to completely exclude the presence of O ₂ and H ₂ O in the reaction involving Cr ²⁺ , and even reagent metering was required to be carried out in a nitrogen atmosphere.

Reactions involving divalent chromium (Cr ²⁺ ) were always performed in the absence of light as much as possible to prevent cis / trans isomerization.

Preparation Example of Vitamin D Derivative of Formula (I)

Vitamin D derivatives of formula (I) obtained according to the obtaining method of the present invention are shown in Tables 1 and 2.

Table 1. Examples of Derivatives of Formula (I) wherein D = CR ₅ R ₆ Y Obtained

In all cases, for p ≠ 0, R ₃ = R ₄ = H

Table 2. Example of Derivative of Formula (I) With D = C (O) R ₅ Obtained

(Ib)

1. Preparation of a compound of formula (I) wherein M = 0, n = 1, p = 0 or 1, and Y = OH

Section A: p = 0

Method 1A / 1: Compounds (1), (2), (3), (4), (5) and (6)

Step 1a: Compound (1)

15 ml of 1.5 M LDA was added dropwise to a solution of 2.30 g of iodine derivative (IIA2a) in 25 ml of anhydrous THF and cooled at −70 ° C. for 1 hour, keeping the temperature no higher than −65 ° C. When the addition is complete, stir for 5 minutes and add 5 ml of water. The temperature was left to increase to 0 ° C. and the mixture was dispersed between 200 ml of EBM and 150 ml of NH ₄ Cl. The organic phase was separated and washed twice with 100 ml of brine each. The crude was eluted with hexanes / Cl ₂ CH 2 10: 1 and 4: 1 and purified by flash chromatography. Fractions containing the product were combined and concentrated to give 1.63 g of a white solid (87% yield).

Step 1b: Compound (1)

A solution of 1.4 g of iodine derivative (IIA2a) in 10 ml of EBM and 30 ml of DMSO was heated to 55-60 ° C. and 2.24 g of potassium tert -butoxide was added in small portions. At the end of the reaction (typically 60 to 90 minutes), 100 ml of EBM are added, washed with NH ₄ Cl solution, washed three times with 100 ml of brine each, dried and placed in a rotary evaporator. The crude is eluted with 1: 1 hexanes / ether and EBM and purified by flash chromatography. Fractions containing the product were collected, concentrated and re-silylate with tetrabutylsilyl chloride / imidazole to give 636 mg of a white solid (93% yield).

Compound (1)

¹ H NMR

0.06 (s, 12H (CH ₃ -Si)), 0.57 (s, 3H (C-18)), 0.87 and 0.90 (2 s, 18H ((CH ₃ ) ₃ C)), 1.24 (d, J: 7 Hz, 3H (C-21)), 2.03 (d, J: 116 Hz, 1H (C-23)), 4.22 (m, 1H (C-3)), 4.53 (m, 1H (C-1)) , 4.97 (d, J: 9 Hz, 2H (C-19)), 5.83 (d, J: 11 Hz, 1H (C-7)), 6.455 (d, J: 11.2 Hz, 1H (C-6)) ppm

IR (KBr)

3313 and 2106 (C≡CH), 1255, 1084, 837 and 724 (TBDMS group), 1170 (CO), 908 (= CH ₂ ) cm ^-1

Compound (2)

Alkyne (2) is obtained using iodine derivative (IIA3) as a starting material.

NMR (CDCl ₃ )

0.06 (s, 12H (CH ₃ -Si)), 0.56 (2, 3H (C-18)), 0.88 (s, 18H ((CH ₃ ) ₃ C), 1.20 (d, J = 6.6 Hz, 3H ( C-21)), 2.02 (d, J = 2.4 Hz, 1H (C-23)), 4.19 (m, 1H (C-3)), 4.38 (m, 1H (C-1)), 4.86 (d , J = 2.6 Hz, 1H (C-19)), 5.48 (s, 1H (C-19)), 5.28 (d, J = 11.2 Hz, 1H (C-7)), 6.30 (d, J = 11.8 Hz) ppm.

IR (KBr)

3320 and 2112 (C≡CH), 1255, 1084, 837 and 724 (TBDMS group), 908 (= CH ₂ ) cm ^-1

Step 1a + Step 2a: Compounds (3) and (4)

14 g (20 mmol) of compound IIA2 are dissolved in 100 ml of dry THF under N2 atmosphere. Cool to −78 ° C. and add 1.5 M LDA in cyclohexane to the dropwise method by cannula, keeping the temperature below −70 ° C. until at least 90% of the iodine derivative is converted to alkyne.

Stir for 1 hour while maintaining the temperature, stir and raise the temperature to +5 ° C. Add the LDA of eastern blood, stir at that temperature for 15 minutes, and cool to -70 ° C again. After cooling, 3.2 g of cyclopropanecarboxamide of N, N -dimethylhydroxylamine is added dropwise for 10 minutes. Stir at that temperature for 1 hour and stir at 0 ° C. for 1 hour.

Finally dispersed between diluted bicarbonate and hexanes, the organic phase was dried and eluted with an increasing mixture of AcOEt in 0.5% to 3% hexanes and purified by medium pressure flash chromatography. In this way, 9.8 g (74%) of propargyl ketone (3) (white crystals) and 2.4 g of alkyne (1) (20.2% recovery) were obtained.

Ketone (4) was obtained in a similar manner using alkyne IIA3a as starting material.

Compound 3

NMR (CDCl ₃ )

0.065 (s, 12H (CH ₃ -Si)), 0.58 (s, 3H (C-18), 0.86 and 0.90 (2s, 18 H (CH ₃ ) ₃ C)), 1.00 and 1.21 (2 m, 4H ( C ₂₆ + C ₂₇ ), 1.28 (d, J = 6.8 Hz, 3H (C-21)), 2.63 (m, 1H, (C-25)), 4.23 (m, 1H (C-3)), 4.54 (m, 1H (C-1), 4.95 and 4.99 (2s, 2H (C-19)), 5.84 (d, J = 11.8 Hz, 1H (C-7)), 6.45 (d, J = 11.8 Hz, 1H (C-6)) ppm.

IR (KBr)

2220 (C≡C), 1255, 1084, 837 and 724 (TBDMS groups), 1664 (C = O), 1120 (CO), 908 (C = CH ₂ ) cm ^-1 .

Compound (4)

NMR (CDCl ₃ )

0.06 (s, 12H (CH ₃ -Si)), 0.58 (s, 3H (C-18), 0.86 and 0.90 (2s, 18 H (CH ₃ ) ₃ C)), 1.00 and 1.20 (2 m, 4H ( C ₂₆ + C ₂₇ ), 1.27 (d, J = 6.8 Hz, 3H (C-21)), 2.63 (m, 1H, (C-25)), 4.20 (m, 1H (C-3)), 4.39 (m, 1H (c-1), 5.18 and 5.32 (2s, 2H (C-19)), 5.02 (d, J = 11.8 Hz, 1H (C-7)), 6.24 (d, J = 11.8 Hz, 1H (C-6)) ppm.

IR (KBr)

2220 (C≡C), 1255, 1084 (bb includes CO stretch), 837 and 724 (TBDMS group), 1664 (C = O), 1120 (CO), 908 (C = CH ₂ ) cm ^-1 .

Step 3a: Compounds (5) and (6)

Of, 5.792 g (18.1 mmol) metering in N ₂ atmosphere (+) - Insert the DIP- chloride to the flask in N ₂ atmosphere and cool to -40 ℃. After cooling, 3.1 mg (4.86 mmol) of propargyl ketone (3) in 15 ml of anhydrous ether was added, followed by addition of 1.82 g (2 ml, 18.1 mmol) of N-methylmorpholine. And the internal temperature of the reaction is adjusted to -15 ° C.

The samples are taken every hour and analyzed by HPLC, taking into account that the samples are finished after 6 hours (ketone <15%).

5 ml of acetaldehyde in 5 ml of hexane are added and stirred at −10 ° C. for 30 minutes. After stirring, 200 ml of hexane and 200 ml of t-butylmethyl ether are added and washed twice with 200 ml of brine, respectively.

The organic phase is stirred for 20 minutes with 10 ml of 6N NaOH and finally extracted with 100 ml of 3N NaOH. The organic phase is washed again with diluted bicarbonate, dried over anhydrous MgSO ₄ and concentrated until 8.6 g of oil is obtained.

The oil was eluted with 3% to 15% hexane / t -butylmethylether increasing mixture and clarified by medium pressure flash chromatography. 2.34 g of propargyl alcohol (5) was thus obtained ( S / R = 2.46; clean oil; 75.4% yield) and 180 mg of ketone was recovered (5.8% recovery).

Propargyl ketone (4) was used as starting material to obtain the corresponding R / S alcohol (6).

Compound (5)

NMR (CDCl ₃ )

0.06 (s, 12H (CH ₃ -Si)), 0.38-0.6 (m, 4H (C-CH ₂ )), 0.56 (s, 3H (C-18)), 0.86 and 0.90 (2s, 18H (CH ₃₎ ) ₃ C)), 1.22 (t, J = 7 Hz, 1H (C-CH)), 1.24 (d, J = 7 Hz, 3H (C-21)), 4.22 (m, 1H (C-3) ), 4.29 (m, 1H (C-24)), 4.53 (m, 1H (C-1)), 4.95 and 4.99 (2s, 2H (C-19)), 5.83 (d, J = 11.6 Hz, 1H (C-7)), 6.45 (d, J = 11.6 Hz (C-6)) ppm.

IR (KBr)

3650-3100 (OH), 1255, 1084, 837 and 724 (TBDMS group), 965 ( trans CH = CH), 897 (C = CH ₂ ) cm ^-1 .

Compound (6)

NMR (CDCl ₃ )

0.06 (s, 12H (CH ₃ -Si)), 0.38-0.6 (m, 4H (C-CH ₂ )), 0.55 (s, 3H (C-18)), 0.88 (s, 18H (CH ₃ ) ₃ C)), 1.19 (t, J = 6.8 Hz, 3H (C-21)), 1.23 (sc, 1H (C-CH)), 4.19 (m, 1H (C-3)), 4.27 (m, 1H (C-24)), 4.38 (m, 1H (C-1)), 5.18 and 5.32 (2s, 2H (C-19)), 5.02 (d, J = 11.4 Hz, 1H (C-7)), 6.24 (d, J = 11.4 Hz, 1H (C-6)) ppm.

IR (KBr)

3650-3100 (OH), 1255, 1084 (bb includes CO stretching), 837 and 729 (TBDMS group), 989 ( trans CH = CH), 908 (C = Ch ₂ ) cm ^-1 .

Section B: p = 1

Method 1B / 1: Compound (7)

1.5 M LDA in cyclohexane is added to 350 mg (0.5 mmol) of a solution of iodine derivative (IIA2a) in 10 ml of dry THF until at least 90% of the starting material is converted to alkyne. After addition, eastern blood LDA was added to form a lithium salt, stirred for 60 minutes, cooled to −40 ° C., and 5 ml of DMPU and 360 mg (443 μl, 5 mmol) of isobutylene oxide Add. The ambient temperature is left to rise and stirred for 12 hours.

The crude is dispersed between hexanes and brine and the organic phase is washed with water and sodium sulfite, dried over Na ₂ SO ₄ and concentrated.

The crude was eluted with hexane / AcOEt mixture (10: 1, 7: 1 and 4: 1) and purified by flash chromatography, 119 mg (7) (34%) and 153 mg alkyne (1) ( 54%).

NMR (CDCl ₃ )

0.04 (s, 12H, (CH ₃ -Si)), 0.55 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)), 1.19 (d, J = 6.9 Hz, 3H (C-21)), 1.26 (s, 6H (C-26 + C-27)), 2.31 (d, J = 2.4, 2H (C-24)), 4.20 (m, 1H (C- 3)), 4.52 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.81 (d, J = 11.4 Hz, 1H (C-7)), 6.43 (d , J = 11.4 Hz, 1H (C-6)) ppm.

IR (KBr):

3645-3770 (OH), 1255, 1084, 837 and 724 (TBDMS groups), 1120 (CO), 906 (= CH ₂ ) cm ^-1 .

2. Preparation of Compounds of Formula (I) wherein m = 1, n = 0 and Y = H

Method 2/1: Compounds (17) and (18)

Compound (17)

350 mg (0.5 mmol) of iodine derivative (IIA2a) and 50 mg (0.04 mmol) of tetrakis triphenylphosphine palladium are added to a 10 ml vial with septum closure. A nitrogen atmosphere is formed, and after forming 2 ml of anhydrous THF, 2 ml of anhydrous C ₆ H ₆ and 2 ml (2 mmol) of 1M diethylzinc in hexane are added using a syringe. Stir at room temperature for 4 hours until the starting material (HPLC // 4% heptane / dichloroethane, iodine derivative <1%) disappears.

Disperse between 50 ml of hexane and 50 ml of brine and filter through Celite. The organic phase is washed with brine, dried over anhydrous Na ₂ SO 4 and filtered through 50 g of fast silica gel, eluting with 2% hexanes / ethyl acetate (AcOEt) until eluting the entire main product. The result was eluted with 0.1% hexanes / AcOEt and purified by high-resolution chromatography to give 269 mg of white crystals (90% yield).

NMR (CDCl ₃ )

0.04 (sa, 12H (CH ₃ -Si), 0.53 (2, 3H (C-18)), 0.85 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)), 0.93 (t, J = 7.2 Hz, 3H (C-25)), 0.99 (d, J = 6.6 Hz, 3H (C-21)), 1.95 (m, 2H, (C-24)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.19 and 5.24 (dd, J = 15 and 15.3 Hz, 1H (C-22)), 5.32 and 5.37 (dt, J = 6 Hz 15.3 HZ, 1H (C-23)), 5.80 (d, J = 11.4 Hz, 1H (C-7)), 6.45 (d, J = 11.1 Hz, 1H (C-8) ) ppm

IR (KBr)

1255, 1084, 837 and 724 (TBDMS group), 1117 (C-0), 968 (CH = CH trans ), 895 (= CH ₂ ) cm ^-1

Compound (18)

700 mg (1 mmol) of iodine derivative (IIA2a) and 100 mg (0.085 mmol) of tetrakis triphenylphosphine palladium and 2 ml of anhydrous benzene are added to a 10 ml vial with septum closure and until completely dissolved Stir.

640 mg (2 mmol) of anhydrous zinc iodine and 3 ml of anhydrous tetrahydrofuran are placed in a 25 ml flask. Cool with ice and add 2 M isobutyl magnesium bromine in 1 ml (2 mmol) ethyl ether to form a white precipitate. Stir at room temperature for 30 minutes, after stirring the contents of the vial are added via syringe.

Stir at room temperature for 4 hours until the starting material (HPLC / 4% heptane / dichloroethane, iodine derivative <1%) disappears.

Disperse between 50 ml of hexane and 50 ml of brine and filter through Celite. The organic phase is washed with brine, dried over anhydrous Na ₂ S0 ₄ and filtered through 50 g of fast silica gel, eluting with 2% hexanes / AcOEt until eluting the entire main product. The result was eluted with 0.1% hexanes / AcOEt and purified by high-resolution chromatography to give 269 mg of white crystals (90% yield).

The result was eluted with 0.1% hexanes / AcOEt and clarified by high-resolution chromatography to give 544 mg of white crystals (87% yield).

NMR (CDCl ₃ )

0.04 (sa, 12H (CH ₃ -Si)), 0.53 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)), 0.85 (2d, J = 6.6 Hz , 6H (C-26 + C-27)), 1.00 (d, J = 6.6 Hz, 3H (C-21)), 1.82 (m, 2H (C-24)), 4.20 (m. 1H (C- 3)), 4.51 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.17 and 5.22 (dd, J = 15.3 Hz, 1H (C-22)), 5.26 And 5.31 (dt, J = 6.9 Hz and 15 Hz, 1H (C-23)), 5.80 (d, J = 11.4 Hz, 1H (C-7)), 6.44 (d, J = 11.4 Hz, 1H (C -6)) ppm.

IR (KBr)

1255, 1084, 837 and 724 (TBDMS group, 1117 (CO), 968 (CH = CH trans ), 895 (= CH ₂ ) cm ^-1

3. Preparation of Compounds of Formula (I) wherein m = 1, n = 0, p = 0 and Y = OH

Method 3/1: Compounds (19), (20), (21), (22), (23), (24), (25) and (26)

3 ml of 1.7 M (5.1 mM) t -butyl lithium is added dropwise to a solution of 3.48 g (5 mM) of the corresponding iodine derivative (IIA2a) or (IIA3a) in 40 ml of anhydrous ether and the temperature is -70 Cool to -78 deg. C while avoiding rising above deg. The reaction is controlled by HPLC and 0.3 ml of t -butyl lithium is added until the starting material disappears. Hold at −78 ° C. for 10 minutes, after which 6.25 mmol of the corresponding aldehyde is added dropwise. After 1 hour, 5 ml of concentrated NH ₄ Cl solution is added, the temperature is raised to 0 to + 5 ° C., brine is added, and the organic phase is washed with sodium sulfite solution, dried, concentrated and separated. .

The crude is eluted with a 12: 1 to 4: 1 hexane / AcOEt mixture and purified by flash chromatography.

Yield: 85-92% with R / S isomer (1: 1) mixture

Compound 19

NMR (CDCl ₃ )

0.065 (s, 12H (CH ₃ -Si)), 0.15-0.65 (m, 4H (c-CH ₂ )), 0.57 (s, 3H (C-18)), 0.87 and 0.90 (2s, 18H ((CH ₃ ) ₃ )), 0.95 (m, 1H (c-CH)), 1.05 (d, J: 6.8 Hz, 3H (C-21)), 3.47 (m, 1H (C-24)), 4.21 (m , 1H (C-3)), 4.55 (m, 1H (C-1)), 4.96 (m, 2H (C-19)), 5.49 (m, 2H (C-22 / C-23)), 5.82 (d, J: 11.2 Hz, 1 H (C-7)), 6.47 (d, J: 11.2 Hz, 1 H (C-6)).

IR (KBr)

3650-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups) 1117 (CO stretch), 976 ( trans CH = CH) and 905 (= CH ₂ ) cm ^-1 .

Compound 20

NMR (CDCl ₃ )

0.065 (s, 12H (CH ₃ -Si)), 0.57 (s, 3H (C-18), 0.87 and 0.90 (2s, 27H, (CH ₃ ) ₃ C)), 1.05 (d, J: 6.8 Hz, 3H (C-21)), 3.67 (m, 1H (C-24)), 4.21 (m, 1H (C-3)), 4.54 (m, 1H, (C-1)), 4.96 (m, 2H (C-19)), 5.45 (m, 2H (C-22 / C-23)), 5.82 (d, J: 11.2 Hz, 1H (C-7)), 6.45 (d, J: 11.2 Hz, 1H (C-6)).

IR (KBr)

3650-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups) 1117 (CO stretch), 976 ( trans CH = CH) and 905 (= CH ₂ ) cm ^-1 .

Compound 21

NMR (CDCl ₃ )

0.061 (s, 12H (CH ₃ -Si)), 0.13-0.60 (m, 4H (c-CH ₂ )), 0.55 (s, 3H, (C-18)), 0.88 and 0.90 (2s, 18H (( CH ₃ ) ₃ C)), 0.8-0.94 (m, 1H (c-CH)), 1.05 (d, J: 6.8 Hz, 3H (C-21)), 3.46 (m, 1H (C-24)) , 4.19 (m, 1H (C-3), 4.38 (m, 1H (C-1)), 4.87 (m, 1H (C-19)), 5.18 (m, 1H (C-19)), 5.49 ( m, 2H (C-22 / C-23)), 6.01 (d, J: 11.4 Hz, 1H (C-7)), 6.24 (d, J: 11.4 Hz, 1H (C-7)) ppm.

IR (KBr)

3650-3125 (OH), 1255, 1084, 837, and 724 (a broad band of bands were observed, including CO stretching at the center of the TBDMS group, or 1084), 975 ( trans CH = CH) and 909 (= CH ₂ ) cm ^-1 .

Compound 22

NMR (CDCl ₃ )

0.061 (s, 12H (CH ₃ -Si)), 0.55 (s, 3H (C-18)), 0.87 (d, J: 7.0 Hz, 6H (C-26 / C-27)), 0.88-0.90 ( 2s, 18H ((CH ₃ ) ₃ C)), 1.05 (d, J: 6.8 Hz, 3H (C-21)), 3.63 (m, 1H (C-24)), 4.20 (m, 1H (C- 3)), 4.36 (m, 1H (C-1)), 4.86 (m, 1H (C-19)), 5.17 (m, 1H (C-19)), 5.45 (m, 2H (C-22 / C-23)), 6.00 (d, J: 11.4 Hz, 1H (C-7)), 6.24 (d, J: 11.4 Hz, 1H (C-6)) ppm.

IR (KBr)

3650-3125 (OH), 1255, 1084, 837, and 724 (TBDMS groups, broad bands with CO stretching at the center of 1084 were observed), 975 ( trans CH = CH) and 909 (= CH ₂ ) cm ^-1 .

Compound 23

NMR (CDCl ₃ )

0.066 (s, 12H (CH ₃ -Si)), 0.56 (s, 3H (C-18)), 0.87 and 0.90 (2s, 18H ((CH ₃ ) ₃ C)), 1.05 (d, J: 6.8 Hz , 3H (C-21)), 3.74 (m, 1H (C-24)), 4.21 (m, 1H (C-3)), 4.55 (m, 1H (C-1)), 4.96 (m, 2H (C-19)), 5.42 (m, 2H (C-22 / C-23)), 5.81 (d, J: 11.2 Hz, 1H (C-7)), 6.45 (d, J: 11.4 Hz, 1H (C-6)) ppm.

IR (KBr)

3650-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups) 1117 (CO stretch), 976 ( trans CH = CH) and 905 (= CH ₂ ) cm ^-1 .

Compound 24

NMR (CDCl ₃ )

0.066 (s, 12H (CH ₃ -Si)), 0.56 (s, 3H (C-18)), 0.87 (d, J: 7.0 Hz, 6H (C-26 / C-27)), 0.88-0.90 ( 2s, 18H ((CH ₃ ) ₃ C)), 1.05 (d, J: 6.8 Hz, 3H (C-21)), 3.69 (m, 1H (C-24)), 4.21 (m, 1H (C- 3)), 4.55 (m, 1H (C-1)), 4.96 (m, 2H (C-19)), 5.49 (m, 2H (C-22 / C-23)), 5.81 (d, J: 11.2 Hz, 1 H (C-7)), 6.47 (d, J: 11.2 Hz, 1 H (C-6)) ppm.

IR (KBr)

3650-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups) 1117 (CO stretch), 976 ( trans CH = CH) and 905 (= CH ₂ ) cm ^-1 .

Compound 25

NMR (CDCl ₃ )

0.066 (s, 12H (CH ₃ -Si)), 0.55 (s, 3H (C-18)), 0.88 (s, 18H ((CH ₃ ) ₃ C)), 1.04 (d, J: 6.8 Hz, 3H (C-21)), 3.76 (m, 1H (C-24)), 4.19 (m, 1H (C-3)), 4.36 (m, 1H (C-1)), 4.86 (m, 1H (C -19)), 5.17 (m, 1H (C-21)), 5.42 (m, 2H (C-19)), 6.01 and 6.23 (2d, J: 11.4 Hz, 2H (C-6 / C-7) ) ppm.

IR (KBr)

3650-3125 (OH), 1255, 1084, 837, and 724 (TBDMS groups, broad bands with CO stretching at the center of 1084 were observed), 975 ( trans CH = CH) and 909 (= CH ₂ ) cm ^-1 .

Compound 26

NMR (CDCl ₃ )

0.066 (s, 12H (CH ₃ -Si)), 0.56 (s, 3H (C-18)), 0.88 and 0.90 (2s, 27H ((CH ₃ ) ₃ C)), 1.04 (d, J: 6.8 Hz , 3H (C-21)), 3.65 (m, 1H, (C-24)), 4.21 (m, 1H (C-3)), 4.35 (m, 1H (C-1)), 4.86 (m, 1H (C-19)), 5.16 (m, 1H (C-19)), 5.45 (m, 2H (C-22 / C-23)), 5.99 (d, J: 11.4 Hz, 1H (C-7 )), 6.24 (d, J: 11.4 Hz, 1H (C-6)) ppm.

IR (KBr)

3650-3125 (OH), 1255, 1084, 837, and 724 (TBDMS groups, broad bands with CO stretching at the center of 1084 were observed), 975 ( trans CH = CH) and 909 (= CH ₂ ) cm ^-1 .

Method 3/2: Compounds (19) and (21)

2.55 g (4 mmol) of propargyl alcohol (5) and 25 ml of anhydrous tetrahydrofuran are placed in a cylinder and the temperature of the bath is heated to 70 ° C. 432 mg (8 mmol) of sodium methoxide suspension are added dropwise to 8 ml of 2.1 g (6.8 mmol) of 65% Redal or to 1 ml of lithium hydride and aluminum hydride solution in tetrahydrofuran. The addition is carried out for 15 minutes and analyzed every 15 minutes. The reaction is considered terminated when the amount of saturated alcohol exceeds 1.5%. Transfer to a mixture of hexane / t-butylmethyl ether (300/150 ml) and 350 ml of 0.1 N sulfuric acid. The organic phase was separated, washed with brine and sodium carbonate, dried and concentrated to yield 2.8 g of an oily crude. The resultant was eluted with 10% hexanes / AcOEt and purified by high-resolution chromatography, 0.32 g of the starting material propargyl alcohol (12.5% recovery), 0.61 g of allyl alcohol (19) (R isomer) (23.8% Yield) and 1.51 g of allyl alcohol 19 (S isomer) (59% yield).

The corresponding alcohol 21 could be obtained from the alcohol 6 in a similar manner.

Method 3/3: Compounds (33), (34) and (35)

1 mmol of the corresponding aldehyde and 0.5 mmol of the iodine derivative (IIA1a) or the iodine derivative (IIA1b) diluted in an amount of DMF (0.5 to 1 ml, if the reagent is not DMF-soluble, they are diluted in anhydrous THF) The mixture of was placed in a flask containing 308 mg of CrCl ₂ (2.5 mmol), 0.3 mg of NiCl ₂ and 10 ml of anhydrous DMF, while the temperature did not exceed 25 ° C. The reaction is periodically controlled by HPLC, and when there is no further progress in the reaction, brine is added and extracted with hexanes. The upper phase (upper phase) is washed twice with sodium sulfite solution, dried and concentrated.

The resulting crude is eluted with hexane / AcOEt mixture and purified by flash chromatography. The starting iodine derivative could be recovered from the most nonpolar fractions by preparative chromatography.

Compound (33)

NMR (CDCl ₃ )

0.02, 0.04 and 0.05 (3 s, 12 H (CH ₃ -Si)), 0.16, -0.65 (m, 4H (C-CH ₂ )), 0.68 and 0.58 (minor isomer) (s, 3H (C-18)), 0.87 and 0.90 (2s, 18H (CH ₃ ) ₃ C)), 0.95 (m, 1H (C-CH)), 1.09 (d, J = 6.8 Hz, 3H (C-21) ), 3.47 (m, 1H (C-24)), 3.75 (qAB, J = 16 Hz, 2H (C-19), 4.16 (m, 1H (C-3)), 4.34 (m, 1H (C- 1)), 4.66 and 4.70 (minority isomers) (qAB, J = 10.2 Hz, 2H (C-6 + C-7)), 5.49 (m, 2H (C-22 + C-23)) ppm.

IR (KBr)

3650-3100 (OH), 1255, 837 and 724 (TBDMS groups), 1317, 1095 (bb includes C-0 and SiO stretch) and 873 (SO ₂ ), 989 ( trans CH = CH) cm ^-1 .

Compound (34)

NMR (CDCl ₃ )

0.02, 0.04 and 0.05 (3 s, 12 H (CH ₃ -Si)), 0.68 and 0.58 (hydroisomers) (S, 3H (C-18)), 0.87 (d, J = 7 Hz, 6H (C-26 / C-27), 0.87 and 0.90 (2s, 18H (CH ₃ ) ₃ C)), 1.05 (d, J = 6.8 Hz, 3H (C-21)), 3.69 (m, 1H (C-24)) , 3.76 (qAB, J = 16 Hz, 2H (C-19), 4.16 (m, 1H (C-3)), 4.34 (m, 1H (C-1)), 4.66 and 4.70 (minorum isomers) (qAB , J = 10.2 Hz, 2H (C-6 + C-7)), 5.49 (m, 2H (C-22 + C-23)) ppm.

IR (KBr)

3700-3100 (OH), 1305 and 1055 (SO ₂ ), 1113 (C-0) and 987 ( trans CH = CH) cm ⁻¹ .

Compound (35)

NMR (CDCl ₃ )

0.16, -0.62 (m, 4H (C-CH ₂ )), 0.67 and 0.56 (minority isomers) (s, 3H (C-18)), 0.95 (m, 1H (C-CH)), 1.05 (d, J = 6.8 Hz, 3H (C-21)), 2.06 and 2.08 (2s, 2x3H (COOCH ₃ )), 3.47 (m, 1H (C-24)), 3.75 (qAB, J = 16 Hz, 2H (C -19), 4.69 (m, 2H (C-6 + C-7)), 5.48 (m, 3H (C-1, C-22 and C-23)) ppm.

IR (KBr)

3600-3100 (OH), 1738 (CO), 1317 and 1037 (SO ₂ ), 1236 (C-0) and 989 ( trans CH = CH) cm ⁻¹ .

Method 3/4: Compounds (33) and (34)

In this way, it can be obtained from the corresponding aldehyde of formula (IV) without isolating the corresponding intermediate of formula (II).

Strict exclusion of oxygen and moisture in a flask with 2 mmol of the corresponding VII- (A1) aldehyde and 4 mmol of I ₃ CH in 15 ml of anhydrous THF and 2.46 CrCl ₂ (20 mM) and 15 ml of anhydrous THF And dropwise added while maintaining the temperature at 0 ° C. Once all the aldehydes have reacted (2 to 3 hours), the solvent is removed under vacuum and at 0 ° C.

25 ml of DMF containing 4 mmol of the corresponding aldehyde and 2 mg of NiCl ₂ are added to the resulting chocolate-light material and stirred at 25 ° C. until no further progress in the reaction (control by HPLC).

Once the reaction is complete, continue as described in Method 3/3.

Method 3/5: Compounds (19), (24) and (32)

A mixture of 2 mmol SO ₂ adducts (33, 34 and 35), 1.5 g of NaHCO ₃ and 150 ml of DMF is heated under an atmosphere of 80 ° C. to N ₂ until the starting material disappears (2-3 hours). 15 ml of water and 150 ml of hexane are added and the upper phase is washed with water, dried and concentrated to prepare compounds (19), (24) and (32) (90% yield).

Method 3/6. Compounds (21), (22), (25), (26) and (31)

UV lamp (for about 1 hour (until the amount of trans compound is less than 5%) in a mixture of 10 mmol of trans derivatives (19, 20, 23, 24 and 32), 1 g of anthracene and 800 ml of toluene Irradiate with Heraeus TQ 150 Z ₂ (Heraeus TQ 150 Z ₂ ).

When the reaction is complete, it is filtered, concentrated in vacuo, the crude is eluted with 10% to 2% hexanes / AcOEt, purified by preparative chromatography, compounds (21), (22), (25), Two R and S isomers of (26) and (31) (produced 1: 1 with a yield of 85% to 93%) were separated

Method 3/7. Compound (27), (28), (29) and (30)

10 mmol of the silylated compound (19, 21, 22 or 24, R, S isomer or mixture thereof) is dissolved in 70 ml of 1 M tetrabutylammonium fluoride (70 mmol) and brought to 60-65 ° C. for 50 minutes. Heat.

When the reaction is complete, it is dispersed between 500 ml of AcOEt and water, and the organic phase is diluted with 300 ml of Cl ₂ CH ₂ , dried over Na ₂ SO ₄ , eluted directly with AcOEt and purified by flash chromatography. . The crude thus obtained was crystallized from methyl formate to obtain 70% of the corresponding compound (27), (28), (29) or (30).

Method 3/8

3/8 a. Compound (28)

Method 3/5 is applied to 2 mmol of compound (35) using anhydrous EtOH instead of DMF. When the reaction is complete, 2 g (50 mmol) of NaOH powder and 15 ml of water are added and stirred at room temperature until the acetate disappears.

When the reaction is complete, ethyl acetate and sufficient water are added until two phases are formed. The upper phase is dried over Na ₂ S0 ₄ , concentrated, eluted with AcOEt, and purified by preparative chromatography to give compound (28) in 85% yield ( R / S isomer mixture).

3/8 b. Compound (27) and (28)

10 ml of 96 ° alcohol and 1.32 g of KOH are added to 1 mol of compound (31) or (32). Stir at room temperature until the acetate disappears. The corresponding compounds (28) and (27) were thus obtained in 95% yield ( R / S isomer mixture).

Compound 27

NMR (CDCl ₃ + 5% CD ₃ OD)

0.15-0.60 (m, 4H (c-CH ₂ )), 0.56 (s, 3H (C-18)), 0.92-1.04 (m, 1H (c-CH)), 1.05 (d, J: 6.6 Hz, 3H (C-21)), 3.43 (m, 1H (C-24)), 4.20 (m, 1H (C-3)), 4.40 (m, 1H (C-1)), 4.99 (m, 1H ( C-19)), 5.32 (m, 1H (C-19)), 5.46 (m, 2H (C-22 / C-23)), 6.02 (d, J: 11.4 Hz, 1H (C-7)) , 6.37 (d, J: 11.4 Hz, 1H (C-6)) ppm.

IR (KBr)

3600-3150 (OH), 1062 and 1029 (CO stretch), 975 ( trans CH = CH) and 910 (= CH ₂ ) cm ⁻¹ .

Compound 28

NMR (CDCl ₃ + 5% CD ₃ OD)

0.15-0.61 (m, 4H (c-CH ₂ )), 0.58 (s, 3H (C-18)), 0.87-1.08 (m, 1H (c-CH)), 1.06 (d, J: 6.6 Hz, 3H (C-21)), 3.41 (m, 1H (C-24)), 4.20 (m, 1H (C-3)), 4.48 (m, 1H (C-1)), 4.97 (m, 1H ( C-19)), 5.12 (m, 1H (C-19)), 5.47 (m, 2H (C-22 / C-23)), 5.89 (d, J: 11.2 Hz, 1H (C-7)) , 6.57 (d, J: 11.2 Hz, 1H (C-6)) ppm.

IR (KBr)

3600-3150 (OH), 1055 and 1029 (CO stretch), 975 ( trans CH = CH) and 906 (= CH ₂ ) cm ^-1 .

Compound 29

NMR (CDCl ₃ + 5% CD ₃ OD)

0.56 (s, 3H (C-18), 0.87 (d, J: 7.0 Hz, 6H (C-26-C-27)), 1.06 (d, J: 6.6 Hz, 3H (C-21)), 1.75 (m, 1H (C-25)), 3.71 (m, 1H (C-24)), 4.20 (m, 1H (C-3)), 4.48 (m, 1H (C-1)), 4.97 (m , 1H (C-19)), 5.12 (m, 1H (C-19)), 5.47 (m, 2H (C-22 / C-23)), 5.89 (d, J: 11.2 Hz, 1H (C- 7)), 6.57 (d, J: 11.2 Hz, 1H (C-6)) ppm.

IR (KBr)

3600-3150 (OH), 1062 and 1029 (CO stretch), 975 ( trans CH = CH) and 910 (= CH ₂ ) cm ⁻¹ .

Compound 30

NMR (CDCl ₃ + 5% CD ₃ OD)

0.56 (s, 3H (C-18)), 0.87 (d, J: 7.0 Hz, 6H (C-26-C-27)), 1.05 (d, J: 6.6 Hz, 3H (C-21)), 1.75 (m, 1H (C-25)), 3.63 (m, 1H (C-24)), 4.20 (m, 1H (C-3)), 4.40 (m, 1H (C-1)), 4.99 ( m, 1H (C-19)), 5.32 (m, 1H (C-19)), 5.46 (m, 2H (C-22 / C-23)), 6.02 (d, J: 11.4 Hz, 1H (C -7)), 6.37 (d, J: 11.4 Hz, 1H (C-6)) ppm.

IR (KBr)

3600-3150 (OH), 1062 and 1029 (CO stretch), 975 ( trans CH = CH) and 910 (= CH ₂ ) cm ⁻¹ .

Compound 31

NMR (CDCl ₃ )

0.22-0.58 (m, 4H (c-CH ₂ )), 0.53 (s, 3H (C-18)), 0.90-1.10 (m, 1H (c-CH)), 1.03 (d, J: 6.6 Hz, 3H (C-21)), 2.03 and 2.05 (2s, 6H (CH ₃ CO)), 3.40 (m, 1H (C-24)), 5.03 (m, 1H (C-19)), 5.18 (m, 1H (C-3)), 5.31 (m, 1H (C-19)), 5.46 (sc, 3H (C-22 / C-23 + C-1)), 5.91 (d, J: 11.4 Hz, 1H (C-7)), 6.35 (d, J: 11.4 Hz, 1H (C-6)) ppm.

Compound 32

NMR (CDCl ₃ )

0.21-0.58 (m, 4H (c-CH ₂ )), 0.55 (s, 3H (C-18)), 0.90-1.09 (m, 1H (C-CH)), 1.04 (d, J: 6.6 Hz, 3H (C-21)), 2.03 and 2.05 (2s, 6H (CH ₃ CO)), 3.40 (m, 1H (C-24)), 5.01 (m, 1H (C-19)), 5.15 (m, 1H (C-19)), 5.18 (m, 1H (C-3)), 5.50 (sc, 3H (C-22 / C-23 + C-1)), 5.82 (d, J: 11.6 Hz, 1H (C-7)), 6.46 (d, J: 11.6 Hz, 1H (C-6)) ppm.

4. Preparation of compounds of formula (I) wherein m = 1, n = 0, p = 1-6

Method 4/1: Compounds (36), (37) and (38)

350 mg (0.5 mmol) of iodine derivative (IIA2a), 15 mg (0.07 mmol) of Ac ₂ Pd and 528 mg (5.5 mmol) of t- BuONa are placed in a 5 ml vial. Seal and add 3 ml of THF, 20 ml of t- Bu ₃ P (about 0.1 mmol) and 580 ml (5 mmol) of acetophenone using a syringe.

After stirring for 1 hour at room temperature, dispersed between hexanes and brine, the organic phase was extracted three times with brine, dried, eluted with 8: 1 hexanes / AcOEt, and purified by flash chromatography to give 275 mg of white color. Obtained compound 36 (80% yield) which is crystalline.

Acetophenone was substituted with 5 mmol of cyclopropyl ketone or 5 mmol of propanone to give compounds (37) and (38) in yields of 58% and 37%, respectively.

Compound (36)

NMR (CDCl ₃ )

0.07 (s, 12H (CH ₃ -Si)), 0.55 (s, 3H (C-18)), 0.87 and 0.91 (2s, 18H ((CH ₃ ) ₃ C)), 1.04 (d, J = 6 Hz , 3H (C-21)), 3.67 (d, J = 6.3 Hz, 2H (C-24)), 4.22 (m, 1H (C-3)), 4.54 (m, 1H (C-1)), 4.95 and 4.99 (2s, 2H (C-19)), 5.42 and 5.45 (dd, J = 15.3 Hz, 1H (C-22)), 5.56 and 5.61 (dt, J = 6.6 Hz and 15.3 Hz, 1H (C -23)), 5.80 (d, J = 11.7 Hz, 1H (C-7)), 6.46 (d, J = 11.4 Hz, 1H (C-6)), 7.4-7.6 (sc, 3H (C-28 + C-29-C-30)), 7.98 (d, J = 7.5 Hz, 2H (C-27 + C-31)) ppm.

IR (KBr)

1255, 1084, 837, 724 (TBDMS group), 1695 (C = O), 1120 (CO), 970 ( trans CH = CH), 895 (= CH ₂ ) cm ^-1

Compound (37)

NMR (CDCl ₃ )

0.04 (s, 12H (CH ₃ -Si)), 0.53 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H (CH ₃ ) ₃ C)), 0.75-0.9 and 0.95-1.05 (sC , 4H (C-27 and C-28)), 1.95 (sC, 1H (C-26)), 3.18 (d, J = 5.7 Hz, 2H (C-24)), 4.20 (m, 1H (C- 3)), 4.51 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.38 and 5.41 (dd, J = 15.3 and 15 Hz, 1H (C-23)) , 5.45 and 5.52 (dt, J = 15.3 and 6.3 Hz, 1H (C-23)), 5.80 (d, J = 11.1 Hz, 1H (C-7)), 6.44 (d, J = 12 Hz, 1H ( C-6)) ppm

IR (KBr):

1255, 1084, 837 and 724 (TBDMS groups), 1705 (C = O), 1120 (CO), 970 (CH = CH), 902 (= CH ₂ ) cm ^-1 .

Compound (38)

NMR (CDCl ₃ )

0.04 (s, 12H, (CH ₃ -Si)), 0.53 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)), 1.02 (d, J = 7.2 Hz, 3H (C-21)), 2.12 (s, 3H (COCH ₃ )), 3.05 (d, J = 5.7, 2H (C-24)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.39 (sc, 2H (C-22 + C-23)), 5.80 (d, J = 11.4 Hz, 1 H (C-7), 6.44 (d, J = 11.7 Hz, 1 H (C-6)) ppm.

IR (KBr):

1716 (C = O), 1255, 1084, 837 and 724 (TBDMS groups), 1118 (CO), 968 ( trans CH = CH), 885 (= CH ₂ ) cm ^-1 .

Method 4/2: Compound 39

This compound was obtained by the same method as described in Method 6B / 1.

Yield: 83% from ketone (7).

NMR (CDCl ₃ )

0.04 (s, 12H, (CH ₃ -Si)), 0.54 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)), 1.02 (d, J = 6.6 Hz, 3H (C-21)), 1.21 (s, 6H (C-26 + C-27)), 2.12 (sc, 2H (C-24)), 4.20 (m, 1H (C-3)), 4.52 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.37 (sc, 2H (C-22 + C-23)), 5.80 (d, J = 11.4 Hz , 1H (C-7)), 6.44 (d, J = 12 Hz, 1H (C-6)) ppm.

IR (KBr):

3600-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups), 1117 (CO), 966 ( trans CH = CH), 902 (= CH ₂ ) cm ^-1 .

5. Preparation of compounds of formula (I) wherein m = 1, n = 1, p = 0, R5 and R6 = alkyl and Y = OH

Method 5/1: Compounds (40), (41), (42), (43), (44) and (45)

Compound (40)

15 mg (0.078 mmol) of cuprous iodide, 15 mg (0.066 mmol) of benzyltriethylammonium chloride and 100 mg (0.086 mmol) of tetrakis triphenylphosphine palladium were added to a flask with N ₂ atmosphere. Put it in.

1.050 g (1.5 mmol) of iodine derivative (IIA2a), 151 mg (175 ml, 1.8 mmol) of 3-methyl-1-butyn-3-ol and 4.5 ml of benzene are placed in a diaphragm vial. Once all material is dissolved, transfer to a flask using a syringe and quickly add 4.5 ml of de-aired 5.5 N NaOH. Stir at room temperature under light conditions for 3 hours 30 minutes, adjusting the reaction with TLC (5% hexanes / AcOEt) until the starting material is substantially gone. The top of the reaction mixture is poured off, the organic phase is diluted with 100 ml of pentane and the solution eluted with 5% and 20% hexanes / AcOEt until no main product is released and filtered over 50 g of fast silica gel.

Fractions containing the main product were put together and placed in a rotary evaporator to obtain 836 mg of white crystals (85%).

NMR (CDCl ₃ )

0.04 (sa, 12H, (CH ₃ -Si)), 0.53 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)), 1.03 (d, J = 6.6 Hz, 3H (C-21)), 1.51 (s, 6H (C-27 + C-28)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (C-1) ), 4.92 and 4.97 (2s, 2H (C-19)), 5.39 (d, J = 15.9 Hz (C-23)), 5.80 (d, J = 11.4 Hz, 1H (C-7)), 5.95 and 5.98 (dd, J = 15.6, 15.9, 1H (C-22)), 6.43 (d, J = 11.1 Hz, 1H (C-6) ppm.

IR (KBr):

3600-3100 (OH), 2221 (C≡C), 1255, 1084, 837 and 724 (TBDMS groups), 1120 (CO), 960 ( trans CH = CH), 895 (= CH ₂ ) cm ^-1 .

Compound (41)

Prepared according to the method described above from 3-methyl-1-pentyn-3-ol. Fast Chromatography Eluent: 12: 1 Hexane / AcOEt and 8: 1 Hexane / AcOEt.

White crystals at 92% yield.

NMR (CDCl ₃ )

0.04 (sa, 12H, (CH ₃ -Si)), 0.53 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)), 1.02 (t, J = 7.5 Hz, 1H (C-29)), 1.03 (d, J = 7.2 Hz, 3H (C-21)), 1.46 (s, 3H (C-27)), 1.67 (m, 2H (C-28 )), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.40 (d, J = 15.9 Hz, 1H (C-23)), 5.80 (d, J = 11.4 Hz, 1H (C-7)), 5.95 and 5.98 (dd, J = 15.9, 1H (C-22)), 6.43 (d, J = 11.4 Hz, 1 H (C-6) ppm.

IR (KBr):

3600-3100 (OH), 2220 (C≡C), 1255, 1084, 837 and 724 (TBDMS group), 1120 (CO), 960 ( trans CH = CH), 897 (= CH ₂ ) cm ^-1 .

Compound (42)

Prepared according to the method described above from 3-methyl-1-pentyn-3-ol. Attribute chromatography Eluent: 12: 1 Hexane / AcOEt.

White crystals at 86% yield.

NMR (CDCl ₃ )

0.04 (sa, 12H, (CH ₃ -Si)), 0.53 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)), 1.01 (t, J = 7.5 Hz, 6H (C ₂₈ + C ₃₀ )), 1.03 (d, J = 6.6 Hz, 3H (C-21)), 1.65 and 1.66 (2q, J = 7.2 and 7.5 Hz, 4H (C-27 + C-29)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.41 (d, J = 15.9 Hz, 1H (C-23)), 5.80 (d, J = 11.7 Hz, 1H (C-7)), 5.96 and 5.98 (dd, J = 15.6 and 15.9, 1H (C-22)), 6.43 ( d, J = 11.4 Hz, 1H (C-6) ppm.

IR (KBr):

3600-3100 (OH), 2220 (C≡C), 1255, 1084, 837 and 724 (TBDMS group), 1120 (CO), 960 ( trans CH = CH), 897 (= CH ₂ ) cm ^-1 .

Compound (43)

Prepared according to the method described above from 1-butyn-3-ol. Attribute chromatography eluent: 8: 1 hexanes / AcOEt and 6: 1 hexanes / AcOEt.

White crystals in 87% yield.

NMR (CDCl ₃ )

0.04 (sa, 12H, (CH ₃ -Si)), 0.53 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)), 1.03 (d, J = 6.6 Hz, 3H (C-21)), 1.45 d, J = 6.6 Hz, 3H (C-27)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (C-1) ), 4.61 (m, 1H (C-26)), 4.92 and 4.97 (2s, 2H (C-19)), 5.41 (d, J = 15.9 Hz, 1H (C-23)), 5.80 (d, J = 11.7 Hz, 1H (C-7)), 5.98 and 6.01 (dd, J = 15.6 and 15.9, 1H (C-22)), 6.43 (d, J = 11.4 Hz, 1H (C-6) ppm.

IR (KBr):

3600-3100 (OH), 2221 (C≡C), 1255, 1084, 837 and 724 (TBDMS groups), 1120 (CO), 960 ( trans CH = CH), 895 (= CH ₂ ) cm ^-1 .

Compound (44)

Prepared according to the method described above from 3-ethyl-1-pentin-3-ol and from cis iodine derivative (IIA3). Attribute chromatography eluent: 6: 1 hexanes / AcOEt.

Foamy solid at 83% yield.

NMR (CDCl ₃ )

0.04 (sa, 12H, (CH ₃ -Si)), 0.52 (s, 3H (C-18)), 0.85 (s, 18H ((CH ₃ ) ₃ C)), 1.02 (d, J = 6.6 Hz, 3H (C-21)), 1.51 (s, 6H (C-27 + C-28)), 4.17 (m, 1H (C-3)), 4.35 (m, 1H (C-1)), 4.83 ( d, J = 2.1 Hz, 1H (C-19)), 5.16 (m, 1H (C-19)), 5.39 (d, J = 15.9 Hz, 1H (C-23)), 5.95 and 5.98 (dd, J = 15.9, 15.6 Hz, 1H (C-22)), 5.98 (d, J = 11.7 Hz, 1H (C-7)), 6.21 (d, J = 11.4 Hz, 1H (C-6) ppm.

IR (KBr):

3600-3200 (OH), 2221 (C≡C), 1255, 1084 (bb include CO stretching), 837 and 724 (TBDMS groups), 989 (trans CH = CH), 908 (CH 2) cm - ¹ .

Compound (45)

Prepared according to the method described above from 3-ethyl-1-pentin-3-ol and from the SO ₂ adduct iodine derivative (IIAla). Fast Chromatographic Eluent: 6: 1 Hexane / AcOEt and 4: 1 Hexane / AcOEt.

Cream-light foam with 85% yield.

NMR (CDCl ₃ )

0.02, 0.04, 0.05 (3s, 12H (CH ₃ -Si)), 0.64 and 0.55 (minor isomers) (s, 3H (C-18)), 0.85 and 0.86 (2s, 18H ((CH ₃ ) ₃ C) ), 1.01 (t, J = 7.5 Hz, 6H (C ₂₈ + C ₃₀ ), 1.03 / d, J = 6.6 Hz, 3H (C-21), 1.65 and 1.66 (2q, J = 7.2 and 7.5 Hz, 4H (C-27 + C-29)), 3.75 (qAB, J = 16 Hz, 2H (C-19)), 4.16 (m, 1H (C-3)), 4.34 (m, 1H (C-1) ), 4.65 and 4.73 (hydroisomers) (qAB, J = 9.6 Hz, 2H (C-6 + C ₇ )), 5.41 (d, J = 15.9 Hz, 1H (C-23)), 5.94 and 5.97 (dd , J = 15.9 Hz (C-22) ppm

IR (KBr)

3600-3200 (OH), 2221 (C≡C), 1255, 1084, 837 and 724 (TBDMS groups), 1317, 1095 and 877 (SO ₂ ), 968 ( trans CH = CH) cm ^-1

6. Prepa ratio n of compounds of formula (I) in which m = 2, n = 0, p = 0.

Section A

Method 6A / 1: Compounds (46) and (47)

Compound (46)

Nitrogen flow through 1,400 mg (2 mmol) of iodine derivative (IIA2a), 690 mg (5 mmol) of anhydrous potassium carbonate, 10 mg of palladium acetate (0.04 mmol) and 600 mg (2 mmol) of tetrabutylammonium chloride Put it in a flask that allows it. 1,400 mg (1.64 ml, 20 mmol) of vinylmethylketone and 2 ml of anhydrous tetrahydrofuran are added. Stir for 5 minutes, add 10 ml of dimethylformamide and stir at room temperature for 4-5 hours until substantially no starting material is detected by TLC (10: 1 hexanes / AcOEt).

The crude is dispersed between 100 ml of hexane and 100 ml of brine and filtered through celite. The organic phase is washed with brine and anhydrous Na ₂ SO ₄ . Filter through eluting with 4: 1 hexanes / AcOEt through 50 g of fast silica gel until the main product elutes. The result was eluted with 5% to 30% hexanes / ethyl acetate and purified by medium pressure chromatography to give 1.1 grams of white crystals (86%).

NMR (CDCl ₃ )

0.04 (sa, 12H (CH ₃ -Si)), 0.55 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)), 1.07 (d, J = 6.6 Hz , 3H (C-21)), 2.24 (s, 3H (COCH ₃ )), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (C-1)), 4.93 and 4.97 (2s, 2H (C-19)), 5.80 (d, J = 11.4 Hz, 1H (C-7)), 6.02 and 6.04 (dd, J = 15 Hz, 1H (C-22)), 6.04 (d, J = 15.3 Hz, 1H (C-25)), 6.11 and 6.14 (dd, J = 15 Hz, 1H (C-23)), 6.43 (d, J = 11.4 Hz, 1H (C-6)), 7.05 and 7.08 (dd, J = 15.6 and 15.9, 1H (C-24)) ppm.

IR (KBr):

1255, 1084, 837, 724 ( TBDMS groups), 1670 (C = O) , 1636 (C = C), 1117 (CO), 1000 ( trans _{(CH = CH) 2),} 906 (= CH 2) cm - ¹ .

Compound (47)

1,400 mg (2 mmol) of iodine derivative (IIA2a), 690 mg (5 mmol) of anhydrous potassium carbonate, 10 mg of palladium acetate (0.04 mmol) and 600 mg (2 mmol) of tetrabutylammonium chloride will be passed through the nitrogen stream. Put it in a flask that allows it.

After loading, 1,720 mg (1.8 ml, 20 mmol) of methyl acrylate and 2 ml of anhydrous tetrahydrofuran are added. Stir for 5 minutes, finally add 10 ml of dimethylformamide and stir 4-5 hours at room temperature until substantially no starting material is detected by TLC (10: 1 hexanes / ethyl acetate).

The crude is dispersed between 100 ml of hexane and 100 ml of brine and filtered through celite. The organic phase is separated, washed with brine and finally dried over anhydrous Na ₂ SO ₄ . The organic phase is filtered by eluting with 10% hexanes / AcOEt through 50 g of fast silica gel until the main product elutes. The result was purified by medium pressure chromatography eluting with 5% hexanes / ethyl acetate to give 1.25 grams of white crystals (95%).

NMR (CDCl ₃ )

0.04 (sa, 12H (CH ₃ -Si)), 0.54 (s, 3H, (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)), 1.06 (d, J = 6.6 Hz, 3H (C-21)), 3.72 (s, 3H (OCH ₃ )), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (C-1)), 4.92 and 4.97 (2s , 2H (C-19)), 5.77 (d, J = 15 Hz, 1H (C-25)), 5.80 (d, J = 11.4 Hz, 1H (C-7)), 5.96 and 5.99 (dd, J = 15 Hz (C-22)), 6.09 and 6.12 (dd, J = 15 Hz (C-23)), 6.43 (d, J = 11.1 Hz (C-6)), 7.21 and 7.25 (dd, J = 15.3 HZ (C-24)) ppm

IR (KBr):

1255, 1084, 837, 724 ( TBDMS groups), 1727 (C = O) , 1644 (C = C), 1138 (CO), 1000 ( trans _{(CH = CH) 2),} 906 (= CH 2) cm - ^One

Section 6B

Method 6B / 1: Compounds (51) and (53)

Compound (51)

400 μl of 1M methyl lithium (0.4 mmol) is added to a solution of 205 mg (0.32 mmol) of (46) in 10 ml of THF, and the reaction is cooled to −70 ° C. while controlled by HPLC (2.6% heptane / AcOEt). Let's do it. Each 100 μL of material added was analyzed and observed that no more alcohol (42% ketone / 56% alcohol) was formed after 400 μL due to ketone enolation.

The reaction crude is dispersed between hexanes and brine, and the organic phase is washed with diluted sodium bicarbonate, dried and concentrated.

The crude was eluted with 10% hexanes / AcOEt and clarified by flash chromatography to yield 85 mg (40%) of alcohol compound (51) and 33 mg of starting material ketone.

In a similar manner, from 327 mg (0.05 mmol) of (47) and 1.25 ml of 0.5M ethyl lithium, 65 mg of alcohol (20% yield) (53) could be obtained, and 200 mg of the starting ester was recovered. It was.

NMR (CDCl ₃ )

0.04 (sa, 12H (CH ₃ -Si)), 0.54 (s, 3H, (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)), 1.03 (d, J = 6.6 Hz, 3H (C-21)), 1.32 (s, 6H (C-27 + C-28)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.53 and 5.56 (dd, J = 15 Hz, 1H (C-22)), 5.69 (d, J = 15.6 Hz, 1H (C-25)), 5.80 (d, J = 11 Hz, 1H (C-7)), 5.92 and 5.95 (dd, J = 15.3 and 15 Hz, 1H (C-23)), 6.12 and 6.16 (dd, J = 15.3 and 15.6 Hz , 1H (C-24)), 6.44 (d, J = 11.4 Hz, 1H (C-6)) ppm

IR (KBr):

3600-3100 (OH), 1255, 1084, 837, 724 (TBDMS group), 1117 (C = O), 989 ( trans (CH = CH) ₂ ), 906 (= CH ₂ ) cm ^-1

Compound (53)

NMR (CDCl ₃ )

0.04 (s, 12H, (CH ₃ -Si)), 0.54 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)), 0.84 (t, J = 7.5 Hz, 6H (C ₂₈ + C ₃₀ )) 1.03 (d, J = 6.6 Hz, 3H (C-21)), 1.53 (q, J = 7.5 Hz, 4H (C-27 + C-29)) , 4.20 (m, 1H (C-3)), 4.51 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.50 (d, J = 15.3 Hz, 1H ( C-25)), 5.51 and 5.54 (dd, J = 15 Hz, 1H (C-22)), 5.87 (d, J = 11.4 1H (C-7)), 5.94 and 5.97 (dd, J = 15 Hz , 1H (C-23)), 6.12 and 6.15 (dd, J = 15 and 15.3 Hz, 1H, (C-24)), 6.44 (d, J = 11.4 Hz, 1H (C-6) ppm.

IR (KBr):

3600-3200 (OH), 1255, 1084, 837 and 724 (TBDMS groups), 1120 (CO), 989 ( trans (CH = CH) ₂ ), 897 (= CH ₂ ) cm ^-1 .

Method 6B / 2: Compounds (48), (49), (50), (51), (52), and (54)

1 mmol of the corresponding iodine derivative, 4.50 mg palladium acetate (0.2 mmol), 652 mg (2 mmol) cesium carbonate, 275 mg (1 mmol) silver carbonate are added to the flask under N2 atmosphere. The diaphragm is installed and 5 ml of anhydrous tetrahydrofuran, 50 ml (about 0.2 mmol) tri- tert -butylphosphine and finally 10 mmol of the corresponding allyl alcohol are added using a syringe.

It is heated at reflux for 4 hours and at room temperature for 12 hours.

The resulting crude is dispersed between 100 ml of pentane and 100 ml of brine and the organic phase is eluted with 8: 1, 6: 1 and 4: 1 hexanes / AcOEt and clarified by medium pressure flash chromatography.

The following compounds were thus obtained:

Compound r ₅ R ₆ Yield Stereochemistry

48 H H 46 5E

49 H CH ₃ 42 5E

50 H C ₂ H ₅ 72 5E

51 CH ₃ CH ₃ 73 5E

52 CH ₃ C ₂ H ₅ 90.5 5E

54 CH ₃ CH ₃ 72 5Z

Compound (48)

The compound is prepared from iodine derivatives (IIA2a) and allyl alcohol (1-propen-3-ol). 46% yield. Clean oil.

NMR (CDCl ₃ )

0.04 (s, 12H, (CH ₃ -Si)), 0.54 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)), 1.03 (d, J = 6.6 Hz, 3H (C-21)), 4.14 (d, J = 5.7 Hz, 2H (C-26)), 4.20 (m, 1H (C-3)), 4.52 (m, 1H (C-1) )), 4.92 and 4.97 (2s, 2H (C-19)), 5.55 and 5.57 (dd, J = 15 Hz, 1H (C-22)), 5.68 and 5.73 (dt, J = 6 and 15.3 Hz, 1H (C-25)), 5.87 (d, J = 11.4 Hz, 1H

(C-7)), 5.95 and 5.99 (dd, J = 15 Hz, 1 H (C-23)), 6.16 and 6.19 (dd, J = 15.3 and 15 Hz, 1H, (C-24)), 6.44 (d, J = 11.4 Hz, 1H (C-6) ppm.

IR (KBr):

3600-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups), 1120 (CO), 985 ( trans (CH = CH) ₂ ), 895 (= CH ₂ ) cm ^-1 .

Compound (49)

The compound is prepared from iodine derivatives (IIA2a) and 1-butene-3-ol.

42% yield. Clean oil.

NMR (CDCl ₃ )

0.04 (s, 12H, (CH ₃ -Si)), 0.54 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)), 1.03 (d, J = 6.6 Hz, 3H (C-21)), 1.26 (d, J = 6.6 Hz, 3H (C-27)), 4.20 (m, 1H (C-3)), 4.31 (m, 1H (C-26) )), 4.52 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.53 and 5.56 (dd, J = 15 Hz, 1H (C-22)), 5.58 and 5.61 (dd, J = 15 Hz, 1H (C-25)), 5.80 (d, J = 11 Hz, 1H (C-7)), 5.23 and 5.95 (dd, J = 15.3 and 15 Hz, 1 H ( C-23)), 6.11 and 6.14 (dd, J = 15.3 and 15 Hz, 1H, (C-24)), 6.43 (d, J = 11.1 Hz, 1H (C-6) ppm.

IR (KBr):

3650-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups), 1120 (CO), 989 ( trans (CH = CH) ₂ ), 895 (= CH ₂ ) cm ^-1 .

Compound (50)

The compound is prepared from iodine derivative (IIA2a) and 1-penten-3-ol.

72% yield. Clean oil.

NMR (CDCl ₃ )

0.04 (s, 12H, (CH ₃ -Si)), 0.54 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)), 0.89 (t, J = 7.2 Hz, 3H (C-28)), 1.03 (d, J = 6.6 Hz, 3H (C-21)), 1.52 (sc, 2H (C-27)), 4.01 and 4.03 (dt, J = 6 And 6.6 Hz, 1H (C-25)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.53, 5.54, 5.55 and 5.56 (2dd, J = 15 Hz, 2H (C-22 + C-25)), 5.80 (d, J = 11 Hz, 1H (C-7)), 5.93 and 5.96 (dd, J = 14.7 Hz, 1 H (C-23)), 6.12 and 6.15 (dd, J = 15 and 15.6 Hz, 1H, (C-24)), 6.44 (d, J = 11.4 Hz, 1H (C-6 ) ppm.

IR (KBr):

3600-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups), 1120 (CO), 989 ( trans (CH = CH) ₂ ), 895 (= CH ₂ ) cm ^-1 .

Compound (51)

The compound is prepared from iodine derivative (IIA2a) and 3-methyl-1-buten-3-ol.

73% yield. Clean oil.

Compound (52)

The compound is prepared from iodine derivatives (IIA2a) and 3-methyl-1-penten-3-ol.

90.5% yield. Clean oil.

NMR (CDCl ₃ )

0.04 (s, 12H, (CH ₃ -Si)), 0.54 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)), 0.86 (t, J = 7.5 Hz, 3H (C-29)), 1.03 (d, J = 6.6 Hz, 3H (C-21)), 1.26 (s, 3H (C-27)), 1.55 (q, J = 7.5 Hz, 2H (C-28)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.52 and 5.55 ( dd, J = 14.7 and 15 Hz, 1H (C-22)), 5.60 (d, J = 15.3 Hz, 1H (C-25)), 5.80 (d, J = 11.4 Hz, 1H (C-7)) , 5.93 and 5.96 (dd, J = 15 Hz, 1 H (C-23)), 6.12 and 6.16 (dd, J = 15.3 Hz, 1H, (C-24)), 6.44 (d, J = 11.7 Hz, 1H (C-6) ppm.

IR (KBr):

3600-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups), 1120 (CO), 989 ( trans (CH = CH) ₂ ), 895 (= CH ₂ ) cm ^-1 .

Compound (54)

The compound is prepared from iodine derivatives (IIA3a) and 3-methyl-1-buten-3-ol.

72% yield. Clean oil.

NMR (CDCl ₃ )

0.04 (sa, 12H, (CH ₃ -Si)), 0.53 (s, 3H (C-18)), 0.85 (s, 18H ((CH ₃ ) ₃ C)), 1.02 (d, J = 6.6 Hz, 3H (C-21)), 1.31 (s, 6H (C-27 + C-28)), 4.17 (m, 1H (C-3)), 4.35 (m, 1H (C-1)), 4.83 ( d, J = 2.7 Hz, 1H (C-19)), 5.15 (m, 1H (C-19)), 5.52 and 5.55 (dd, J = 15.3 and 15 Hz, 1H (C-22)), 5.68 ( d, J = 15.6 Hz, 1H (C-25)), 5.91 and 5.94 (dd, J = 15 Hz, 1H (C-23)), 6.00 (d, J = 11.7 Hz, 1H, (C-27) ), 6.12 and 6.15 (dd, J = 15.3 Hz, 1H (C-24)), 6.21 (d, J = 11.1 Hz, 1H (C-6)) ppm.

IR (KBr):

3600-3100 (OH), 1255, 1084 (bb includes CO stretching), 837 and 724 (TBDMS group), 989 ( trans (CH = CH) ₂ ), 908 (= CH ₂ ) cm ^-1 .

Method 6B / 3: Compounds (49), (51), (52), (53), and (55)

Suspension of 432 mg (8 mmol) of sodium methoxide in 8 ml of 1 M lithium hydride and tetrahydrofuran in tetrahydrofuran was heated at a bath temperature of 70 ° C. and 2.72 g (4 mmol) in 25 ml of anhydrous tetrahydrofuran Alkeno-propargyl alcohol 40 is added. The addition is carried out in 5 minutes.

The reaction is considered to have ended when the amount of saturated alcohol exceeds 1.5%, or when less than 3% of starting material remains (5-7 minutes).

Then transfer to a mixture of hexanes / t -butylmethyl ether (300/150 ml) and 350 ml of 20 N NaOH. The organic phase was separated and washed with brine and sodium carbonate, dried and concentrated to give 2.8 g of an oily crude.

The result was eluted with 10% hexanes / AcOEt and clarified by high pressure chromatography to give 2.48 g of clean oil (Compound 51) (91% yield).

The same method was obtained for each alkyne from alkynes 41, 42 and 43:

Compound (49): clean oil, 91% yield.

Compound (52): clean oil, 92% yield.

Compound (53): clean oil, 95% yield.

Compound (55): clean oil, 92% yield.

NMR and IR spectra follow their structure.

7. Preparation of compounds of formula (I) wherein m = 0, n = 0, p> 2

Triene systems must be protected prior to the hydrogenation process because they cannot be directly hydrogenated.

Method 7/1

Triene systems must be protected prior to the hydrogenation process because they cannot be directly hydrogenated.

Preparation of Unsaturated SO2 Addition Intermediates: Compounds (8) and (16)

2 mmol of the corresponding compound to be hydrogenated in 4 ml of Cl ₂ CH _2- obtained according to the preceding method-are added to 20 ml of liquid SO ₂ and the mixture is kept at -10 ° C for 1 hour. SO ₂ and Cl ₂ CH ₂ are distilled off and the corresponding intermediate is separated as a foam.

Compound (8)

This compound was obtained from compound (7).

NMR (CDCl ₃ )

0.02, 0.04 and 0.05 (3s, 12 H (CH ₃ -Si)), 0.64 and 0.56 (hydroisomers) (s, 3H (C-18)), 0.85 and 0.86 (2s, 18H (CH ₃ ) ₃ C) ), 1.19 (d, J = 7 Hz, 3H (C-21)), 1.26 (s, 6H (C-26 + C-27)), 2.31 (d, J = 2.4 Hz, 2H (C-24) ), 3.74 (qAB, J = 16 Hz, 2H (C-19), 4.16 (m, 1H (C-3)), 4.34 (m, 1H (C-1)), 4.66 and 4.70 (minority isomers) ( qAB, J = 10.2 Hz, 2H (C-6 + C-7)), 5.49 (m, 2H (C-22 + C-23)) ppm.

IR (KBr)

3645-3050 (OH), 1255, 837 and 724 (TBDMS groups), 1317, 1095 (bb includes C-0 and SiO stretch) and 873 (SO ₂ ) cm ⁻¹ .

Compound (16)

This compound was obtained from compound (38).

NMR (CDCl ₃ )

0.02, 0.04 and 0.05 (3s, 12H, (CH ₃ -Si)), 0.64 (s, 3H (C-18)), 0.85 and 0.86 (2s, 18H ((CH ₃ ) ₃ C)), 1.02 (d , J = 6.9 Hz, 3H (C-21)), 2.12 (s, 3H (CH ₃ CO)), 3.04 (d, J = 5.7 Hz, 2H (COCH ₂ )), 3.75 (qAB, J = 16 Hz , 2H (C-19)), 4.16 (m, 1H (C-3)), 4.34 (m, 1H (C-1)), 4.65 (qAB, J = 9.6 Hz, 2H (C-6 + C-) 7)), 5.40 (sc, 2H (C-22 + C-23)) ppm

IR (KBr):

1716 (C = O), 1255, 1076, 837 and 724 (TBDMS groups), 1317, 1095 and 873 (SO ₂ ), 968 ( trans CH = CH) cm ⁻¹ .

Method 7/2

Preparation of Unsaturated SO2 Addition Intermediates: Compounds (11) and (15)

450 mg of 5% Pt / C, 300 mg of sodium bicarbonate and 30 ml of 1: 1 benzene: ethanol are added to the additive intermediate obtained from the previous section or already obtained by any of the methods previously described, Stir under H ₂ atmosphere (1 to 1.5 atmosphere) for 24 hours.

The product can be separated by filtration through celite, after which the solvent is distilled off and concentrated.

Compound (11)

This compound was obtained from compound (16).

NMR (CDCl ₃ )

0.02, 0.04 and 0.05 (3s, 12H, (CH ₃ -Si)), 0.62 and 0.53 (minor isomers) (s, 3H (C-18)), 0.85 and 0.86 (2s, 18H ((CH ₃ ) ₃ C )), 0.89 (d, J = 6.7 Hz, 3H (C-21)), 2.11 (s, 3H (CH ₃ CO)), 2.36 (sc, 2H (CH ₂ CO)), 3.75 (qAB, J = 16 Hz, 2H (C-19)), 4.16 (m, 1H (C-3)), 4.34 (m, 1H (C-1)), 4.65 (qAB, J = 9.6 Hz, 2H (C ₆ -C ₇ )), 4.73 (qAB, J = 10.2 Hz, 2H (C ₆ + C ₇ )) (minor isomers)

IR (KBr):

1720 (C = O), 1255, 1076, 837 and 724 (TBDMS groups), 1317, 1095 and 873 (SO ₂ ) cm ⁻¹ .

Compound (15)

This compound was obtained from compound (8).

NMR (CDCl ₃ )

0.02, 0.04 and 0.05 (3s, 12H (CH ₃ -Si), 0.62 and 0.53 (minor isomers) (s, 3H (C-18), 0.85 and 0.86 (2s, 18 H (CH ₃ ) ₃ C), 0.89 (d, J = 6.8 Hz, 3H (C-21)), 1.20 (s, 6H (C-26 + C-27)), 3.75 (qAB, J = 16 Hz, 2H (C-19)), 4.16 (m, 1H (C-3)), 4.34 (m, 1H (C-1)), 4.65 and 4.72 (minor isomers) (qAB, J = 10 Hz, 2H (C ₆ + C ₇ )) ppm.

IR (KBr)

3600-3100 (OH), 1255, 1076, 837 and 724 (TBDMS groups), 1317, 1095 and 870 (SO ₂ ) cm ⁻¹ .

Method 7/3

Saturated Compound Preparation: Hydrogenated Compounds (9), (10), (12), (13) and (14)

1.5 additional grams of sodium bicarbonate and 30 ml of dimethylformamide are added separately separated in the previous step, or added directly to the solution obtained after hydrogenation and concentration, at 80 ° C. for 3 hours until the starting material disappears. Heat. At the end of the reaction, 30 ml of hexane and 0.5 ml of water are added and the upper phase is washed with water, filtered through celite and dried over anhydrous Na ₂ SO ₄ . Finally concentrated to get the desired compound (yield:> 90%).

Compound (9)

This compound was obtained from compound (34).

NMR (CDCl ₃ )

0.065 (s, 18H (CH ₃ -Si)), 0.52 (s, 3H (C-18), 0.86 (s, 9H (CH ₃ ) ₃ C)), 0.87 (d, J = 7.0 Hz, 6H ( C-26 / C-27)), 0.90 (sc, 12H ((CH ₃ ) ₃ C + C-21)), 4.20 (m, 1H (C-3)), 4.55 (m, 1H (C-0 )), 4.92 and 4.97 (2s, 2H (C-19), 5.81 (d, J , = 11.5 Hz, 1H (C-7)), 6.47 (d, J = 11.5 Hz, 1H (C-6)) ppm.

IR (KBr)

3600-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups), 1117 (C-0) and 898 (= CH ₂ ) cm ^-1 .

Compound (10)

This compound was obtained from compound (15).

The compounds can also be prepared by hydrogenating (8) or by reaction of MeLi to (12) according to method 6B7 / 2.

NMR (CDCl ₃ )

0.04 (s, 12H, (CH ₃ -Si)), 0.52 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)), 0.90 (d, J = 7.2 Hz, 3H (C-21)), 1.21 (s, 6H (C-26 + C-27)), 4.20 (m, 1H (C-3)), 4.52 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.80 (d, J = 11.4 Hz, 1H (C-7)), 6.44 (d, J = 12 Hz, 1H (C-6)) ppm.

IR (KBr):

3600-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups), 1118 (CO), 899 (= CH ₂ ) cm ^-1 .

Compound (12)

This compound was obtained from compound (11).

NMR (CDCl ₃ )

0.04 (s, 12H, (CH ₃ -Si)), 0.52 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)),

0.90 (d, J = 6.7 Hz, 3H (C-21)), 2.12 (s, 3H (COCH ₃ )), 2.36 (2, 3H (CH ₃ CO)), 2.36 (sc, 2H (CH ₂ CO) ), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.80 (d, J = 11.4 Hz, 1H (C-7), 6.44 (d, J = 11.7 Hz, 1H (C-6)) ppm.

IR (KBr):

1720 (C═O), 1255, 1084, 837 and 724 (TBDMS groups), 1118 (CO), 895 (= CH ₂ ) cm ⁻¹ .

Compound (13)

This compound was obtained from compound (17).

NMR (CDCl ₃ )

0.04 and 0.05 (2s, 12H (CH ₃ -Si)), 0.52 (s, 2H (C-18)), 0.83-0.91 (sc, 6H (C-21 + C-25)), 0.84 and 0.88 (2s , 18H (CH ₃ ) ₃ C)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.80 (d, J = 11.4 Hz, 1H (C-7)), 6.44 (d, J = 11.4 Hz, 1H (C-6)) ppm

IR (KBr):

1255, 1084, 837 and 724 (TBDMS group) 1117 (CO), 895 (= CH ₂ ) cm ^-1

Compound (14)

This compound was obtained from compound (18).

NMR (CD Cl ₃ )

0.04 (sa, 12H (CH ₃ -Si)), 0.52 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)), 0.85 (2d, J = 6.6 Hz , 6H (C-26 + C-27)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)) , 5.80 (d, J = 11.7 Hz, 1H (C-7)), 6.44 (d, J = 11.4 Hz, 1H (C-6)) ppm

IR (KBr)

1255, 1084, 837 and 724 (TBDMS groups), 1117 (CO), 895 (= CH ₂ ) cm ^-1

According to the present invention configured as described above, according to the simpler method than the conventional method for synthesizing vitamin D derivatives, it is possible to selectively synthesize into advantageous stereoisomers, thereby increasing stereoselectivity, and minimizing by-products and impurities after synthesis. It is effective to synthesize vitamin D derivatives at low cost by using reagents, catalysts and other additives.

Claims (33)

General Formula (I) (I) As a method of obtaining a vitamin D derivative of In the above formula, A is selected from the residues of the general formulas (A1), (A2) and (A3): (A1) (A2) (A3) In the above formula, Z and Z 'are each independently hydrogen; Hydroxyl; Or hydroxyl protected with a hydroxyl protective group; W is a dienophile; And R ′ ₁ , R ′ ₂ and R ′ ₃ are each independently hydrogen; halogen; Hydroxyl; Hydroxyl protected with a hydroxyl protecting group; C ₁ -C ₆ alkyl optionally substituted with halogen, hydroxyl, cyano or amino; C ₂ -C ₆ alkenyl optionally substituted with halogen, hydroxyl, cyano or amino; Di (C ₁ -C ₃ ) alkyl ethers; Or C ₁ -C ₅ alkyl amino; R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen; C ₁ -C ₈ alkyl; C ₃ -C ₆ cycloalkyl; Or C ₆ -C ₁₄ aryl; D is Hydrogen; In which R ₅ and R ₆ are, independently of each other, hydrogen; C ₁ -C ₈ alkyl; C ₃ -C ₆ cycloalkyl; C ₆ -C ₁₄ aryl; Or a ROR ₇ group in which R ₇ is hydrogen; C ₁ -C ₈ alkyl; C ₃ -C ₆ cycloalkyl; Or C ₆ -C ₁₄ aryl; And Y is hydrogen; Hydroxyl; Hydroxyl protected with a hydroxyl protecting group; Or wherein R ₇ is a —OR ₇ group having the same meaning as described above. CR ₅ R ₆ Y; or, In which R ₅ is C (O) R ₅ having the same meaning as described above; M is an integer selected from 0, 1 and 2; N is an integer selected from 0 and 1; P is an integer selected from 0, 1, 2, 3, 4, 5, and 6; At least one of "m", "n", or "p" is 0, and the sum of "m", "n", and "p" is equal to or greater than 1 ("m" + " subject to n "+" p "> 1); The vitamin D derivative obtaining method, (i) wherein A has the same meaning as described above; And X is a halogen atom selected from chlorine, bromine and iodine (II) Alkenyl monohalo derivatives of In formula (A), M is an alkali metal, and R ₈ and R ₉ are, independently from each other, hydrogen; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkyl silyl; Or C ₃ -C ₆ cycloalkyl M (NR ₈ R ₉ ) Compound of Reaction in a solvent to obtain the corresponding metal alkynylide, which is followed by In which R ₅ has the same meaning as described above R ₅ CON (CH ₃ ) OCH ₃ Compound of, and In which R ₅ has the same meaning as described above R ₅ CHO Reacting with a compound selected from compounds of; Obtaining the compound of formula (I) wherein m = 0, n = 1 and p = 0; or, In formula (B), M is an alkali metal, and R ₁₀ is C ₁ -C ₆ alkyl MOR ₁₀ Metal alkoxides and After reacting in a solvent, reacting, reacting with a silylating agent, and reacting, in which R ₁₀ has the same meaning as described above LiR ₁₀ By reacting with an alkyl lithium compound of Obtaining the corresponding lithium alkynide; After obtaining the lithium alkynide In which R ₅ has the same meaning as described above R ₅ CON (CH ₃ ) OCH ₃ Compound of, and In which R ₅ has the same meaning as described above R ₅ CHO Reacting with a compound selected from compounds of; Obtaining the compound of formula (I) wherein m = 0, n = 1 and p = 0; or In Formula (C), M, R ₈ and R ₉ have the same meanings as described above. M (NR ₈ R ₉ ) Compound of After reacting in the first solvent and reacting, wherein R ₅ and R ₆ have the same meanings as described above With epoxide By reaction in a second solvent; Obtaining the compound of formula (I) wherein m = 0, n = 1 and p = 1; or, (D) in a solvent palladium or nickel complex, and Wherein M 'is selected from Li, Mg, Zn, Al, Zr, B and Sn; T is halogen or C ₁ -C ₅ alkyl; "O" is 0 or 1, which is 0 when M 'is a monovalent metal; And p, R ₃ , R ₄ , R ₅ and R ₆ have the same meanings as described above (T) _o M '(CR ₃ R ₄ ) _p CHR ₅ R ₆ By reaction with an organometallic compound of; Obtaining the compound of formula (I) wherein m = 1, n = 0 and p = 1-6; or, (E) in the formula M ″ is selected from alkali metals, alkaline earth metals, Zn, Cu and Ti; L 'is halogen, C ₁ -C ₅ alkyl, triphenylphosphine, cyanide or sulfosyanide; And "q" is an integer selected from 0, 1, 2, 3, 4, 5 and 6 M "(L ') q React with a compound of In the formula, E is a chemical formula having the same meaning as Is a residue of; v is an integer containing between 1 and the valence of M " M ", L 'and q have the same meaning as described above, "v" + "q" is the following formula provided that it matches the valence of M and / or the coordination number of M " (E) vM "(L) q; To obtain a compound of After obtaining the compound, in which R ₅ and R ₆ have the same meaning as described above R ₅ COR ₆ By reaction with a compound of; Obtaining the compound of formula (I) wherein m = 1, n = 0 and p = 0; or, (F) in the solvent, in the presence of nickel and / or palladium salts, chromium compounds, and Wherein R ₅ and R ₆ have the same meanings as described above R ₅ COR ₆ By reaction with a compound of; Obtaining the compound of formula (I) wherein m = 1, n = 0 and p = 0; or, (G) In a solvent, in the presence of a base, the palladium compound and R ₅ in the formula have the same meanings as described above except for hydrogen CH ₃ COR ₅ By reaction with a ketone of; Obtaining the compound of formula (I) wherein m = 1, n = 0 and p = 1; or, (H) In a solvent, in the presence of a base and optionally complexed copper salt (I), optionally in the presence of a phase transfer catalyst, the palladium compound and wherein R ₅ and R ₆ have the following meanings as defined above Chemical formula CH≡CC (OH) R ₅ R ₆ React with propargyl alcohol of; Obtaining the compound of formula (I) wherein m = 1, n = 1 and p = 0; or, (I) In a solvent, in the presence of a base, optionally in the presence of a phase transfer catalyst, the palladium compound and wherein R ₁ and R ₅ have the same meanings as defined above R ₁ -CH = CH-COR ₅ By reaction with a compound of; Obtaining the compound of formula (I) wherein m = 2, n = 0 and p = 0; or, (J) In the solvent, in the presence of a base and a silver salt, the palladium compound and wherein R ₁ , R ₅ and R ₆ have the same meanings as described above R ₁ -CH = C (OH) R ₅ R ₆ By reaction with a compound of; Obtaining the compound of formula (I) wherein m = 2, n = 0 and p = 0; And, if desired, (ii) converting the compound of formula (I) to another compound of formula (I); How to Obtain Vitamin D Derivatives. The method of claim 1, In the compound of Formula (II), wherein X is an iodine atom How to Obtain Vitamin D Derivatives. The method of claim 1, In the compound of Formula (II), wherein W is SO ₂ How to Obtain Vitamin D Derivatives. The method of claim 1, In the compound of formula (II), Z and Z 'are independently of each other a hydroxy group protected with a hydroxyl group or a hydroxyl protecting group, and R' ₁ , R ' ₂ and R' ₃ are hydrogen at the same time How to Obtain Vitamin D Derivatives. The method of claim 4, wherein Wherein the hydroxyl protecting group is selected from a silyl ether group and a carboxy ester group How to Obtain Vitamin D Derivatives. The method of claim 1, In the compound of formula (II), X is an iodine atom; A is selected from (A1), (A2) and (A3); Z and Z 'are simultaneously hydroxyl groups protected with a hydroxyl protecting group, said protecting group being a silyl ether group or an ester derivative of acetate; And R ' ₁ , R' ₂ and R ' ₃ are hydrogen at the same time How to Obtain Vitamin D Derivatives. The method of claim 1, The compound of formula (II) is represented by the formula: Compound IIA1 (IIA1a) (IIA1b) Compound IIA2 (IIA2a) (IIA2b) Compound IIA3 (IIA3a) (IIA3a) Is selected from the group consisting of Compound IIA1, Compound IIA2, and Compound IIA3, In the above formula, The STBDM or MDBTS is ter--butyldimethylsilyl group; And Ac is an acetyl group How to Obtain Vitamin D Derivatives. The method according to any one of claims 1 to 7, In the compound of general formula (II), wherein the C22-C23 double bond having the trans stereochemistry (trans stereochemistry) How to Obtain Vitamin D Derivatives. The method according to any one of claims 1 to 7, The obtained compound of formula (I) is a compound of formula (I), wherein the compound of formula (I) has a C24, C25 or C26 hydroxy group How to Obtain Vitamin D Derivatives. The method of claim 1, In said alternative (A), Said compound of formula (II) is selected from a compound of formula IIA2 and a compound of formula IIA3 according to claim 7; The compound of formula M (NR ₈ R ₉ ) is selected from the group consisting of lithium-diisopropylamide, lithium-dicyclohexylamide, lithium amide, sodium bis (trimethylsilyl) amide and sodium amide; The solvent is an organic solvent selected from ethers, hydrocarbons, and mixtures thereof, preferably tetrahydrofuran (THF); The general formula R ₅ CON (CH ₃₎ OCH ₃ is an amide of a 2-methyl-propanoic acid N, N-Methoxymethyl-hydroxylamine amide and cyclopropanecarboxylic acid in N, N - methoxymethyl - it is selected from hydroxyl amide ; And The compound of formula R ₅ CHO is selected from 2-methylpropanal and cyclopropanecarboxaldehyde (cyclopropanecarboxaldehyde) How to Obtain Vitamin D Derivatives. The method of claim 1, In said alternative (B), Said compound of formula (II) is selected from a compound of formula IIA2 and a compound of formula IIA3 according to claim 7; The metal alkoxide of the formula MOR ₁₀ is selected from the group consisting of sodium t -butoxide, potassium t -butoxide, sodium t -pentoxide and lithium ethoxide; The solvent is a polar aprotic organic solvent selected from DMSO, DMF, DMPU, HMPT and mixtures thereof; The silylating agent is represented by the formula ClSi (R ₁₁ ) (R ₁₂ ) (R ₁₃ ) As a compound of R ₁₁ , R ₁₂ and R ₁₃ are, independently from each other, hydrogen; C ₁ -C ₈ alkyl; C ₃ -C ₆ cycloalkyl; Or C ₆ -C ₁₄ aryl; Preferably t -butyldimethylsilyl chloride; The alkyl lithium compound of formula LiR ₁₀ is selected from the group consisting of n -butyl lithium and ethyl lithium; The general formula R ₅ CON (CH ₃₎ OCH ₃ is an amide of a 2-methyl-propanoic acid N, N-Methoxymethyl-hydroxylamine amide and cyclopropanecarboxylic acid in N, N - methoxymethyl - it is selected from hydroxyl amide ; And The compound of Formula R ₅ CHO is selected from 2-methylpropanal and cyclopropanecarboxaldehyde How to Obtain Vitamin D Derivatives. The method of claim 1, In said alternative (C), Said compound of formula (II) is selected from a compound of formula IIA2 and a compound of formula IIA3 according to claim 7; The compound of formula M (NR ₈ R ₉ ) is selected from the group consisting of lithium-diisopropylamide, lithium-dicyclohexylamide, lithium amide, sodium bis (trimethylsilyl) amide and sodium amide; The first solvent is ether, preferably THF; The epoxide is iso -butylene oxide; And The second solvent is a polar aprotic organic solvent, preferably DMPU How to Obtain Vitamin D Derivatives. The method of claim 1, In said alternative (D), Said compound of formula (II) is selected from a compound of formula IIA2 and a compound of formula IIA3 according to claim 7; The palladium or nickel complex is dichloro (1,1'-bis (diphenylphosphino) ferrocene) palladium, tetrakis (triphenylphosphine) palladium and dichloro (1,1'-bis (diphenylphosphino) ferrocene) A compound selected from the group consisting of nickel; The solvent is an aprotic organic solvent selected from the group consisting of benzene, toluene, tetrahydrofuran, hexane and mixtures thereof; And The organometallic compound of Formula (T) _o M '(CR ₃ R ₄ ) _p CHR ₅ R ₆ is selected from diethyl zinc and isobutyl magnesium bromine How to Obtain Vitamin D Derivatives. The method of claim 1, In said alternative (E), Said compound of formula (II) is selected from a compound of formula IIA2 and a compound of formula IIA3 according to claim 7; The compound of formula M ″ (L) q is selected from lithium, sodium, potassium, n -butyl lithium, sec -butyl lithium and t -butyl lithium; The solvent is an organic solvent selected from ethers, hydrocarbons, and mixtures thereof, preferably ethyl ether; And The compound of Formula R ₅ COR ₆ is selected from 2-methylpropanal, cyclopropanecarboxaldehyde, t -butanecarboxaldehyde and cyclohexanecarboxaldehyde How to Obtain Vitamin D Derivatives. The method of claim 1, In the above alternative (F), The compound of formula (II) is selected from a compound of formula IIA1, a compound of formula IIA2 and a compound of formula IIA3 according to claim 7, The chromium derivative is selected from chromium halides, chromocene and di-chromocene; The nickel salt is selected from nickel halides and nickel acetylacetonates; Said palladium salt is selected from palladium halides and palladium acetylacetonate; The solvent is a polar aprotic organic solvent selected from DMSO, DMF, DMPU, HMPT, DME and mixtures thereof; And The compound of Formula R ₅ COR ₆ is selected from 2-methylpropanal, cyclopropanecarboxaldehyde, t -butanecarboxaldehyde and cyclohexanecarboxaldehyde How to Obtain Vitamin D Derivatives. The method of claim 1, In the alternative (G) above, Said compound of formula (II) is selected from a compound of formula IIA2 and a compound of formula IIA3 according to claim 7; The palladium compound may be tri- t -butylphosphine, tricyclohexylphosphine, 1,1'-bis (di- t -butylphosphine) ferrocene, diphenylphosphino-2- (di- t -butylphosphine Selective from palladium acetate or chloride complexed with phosphine ligands selected from ethyl ferrocene, triphenylphosphine, ditriphenylphosphine, tetrakis (triphenylphosphine) and tris (dibenzylidenoacetone) dipalladium Palladium salts, or palladium complexes complexed with; The base is (i) a metal alkoxide of formula MOR ₁₀ wherein M is an alkali metal and R ₁₀ is C ₁ -C ₆ alkyl; (ii) R _14, R ₁₅ and R ₁₆ are, independently, hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl of the formula N (R ₁₄₎ (R ₁₅ each Amines of (R ₁₆ ); (iii) a 6 membered heterocyclic base wherein at least 1 is nitrogen; And (iv) an inorganic base selected from alkali metal carbonates and alkali metal hydroxides, preferably sodium t -butoxide; The solvent is a polar organic solvent selected from THF, DMF, benzene, dioxane, acetonitrile and mixtures thereof; And The ketone of the formula CH ₃ COR ₅ is selected from acetophenone, methyl-cyclopropyl ketone and propanone How to Obtain Vitamin D Derivatives. The method of claim 1, The alternative (H) is The compound of formula (II) is selected from a compound of formula IIA1, a compound of formula IIA2 and a compound of formula IIA3 according to claim 7; The palladium compound may be tri- t -butylphosphine, tricyclohexylphosphine, 1,1'-bis (di- t -butylphosphine) ferrocene, diphenylphosphino-2- (di- t -butylphosphine Optionally complexed selected from palladium acetate or chloride complexed with phosphine ligands selected from ethyl ferrocene, triphenylphosphine, ditriphenylphosphine, tetrakis (triphenylphosphine) and tris (dibenzylideneacetone) dipalladium Palladium salts, or palladium complexes; The base is (i) a metal alkoxide of formula MOR ₁₀ wherein M is an alkali metal and R ₁₀ is C ₁ -C ₆ alkyl; (ii) R _14, R ₁₅ and R ₁₆ are, independently, hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl of the formula N (R ₁₄₎ (R ₁₅ each Amines of (R ₁₆ ); (iii) a 6 membered heterocyclic base wherein at least 1 is nitrogen; And (iv) an inorganic base selected from alkali metal carbonates and alkali metal hydroxides, preferably sodium t -butoxide; The phase transfer catalyst is an alkyl ammonium halide, preferably tetrabutylammonium chloride; Said selectively complexed copper salt (I) is selected from CuBr, CuI optionally complexed with a phosphine ligand, preferably triphenylphosphine; The solvent is selected from the base and aromatic hydrocarbons, preferably from benzene or toluene; And The propargyl alcohol is selected from 3-methyl-1-butyn-3-ol, 3-methyl-1-pentin-3-ol, 3-ethyl-1-pentin-3-ol and 1-butyn-3-ol That How to Obtain Vitamin D Derivatives. The method of claim 1, In the above alternative (I), The compound of formula (II) is selected from a compound of formula IIA1, a compound of formula IIA2 and a compound of formula IIA3 according to claim 7; The palladium compound may be tri- t -butylphosphine, tricyclohexylphosphine, 1,1'-bis (di- t -butylphosphine) ferrocene, diphenylphosphino-2- (di- t -butylphosphine Optional selected from palladium acetate or chloride complexed with phosphine ligands selected from ethyl ferrocene, triphenylphosphine, ditriphenylphosphine, tetrakis (triphenylphosphine) and tris (dibenzylidene-acetone) dipalladium Palladium salts, or palladium complexes complexed with; Preferably palladium acetate optionally complexed with triphenylphosphine or tri- t -butylphosphine; The base is (i) a metal alkoxide of formula MOR ₁₀ wherein M is an alkali metal and R ₁₀ is C ₁ -C ₆ alkyl; (ii) R _14, R ₁₅ and R ₁₆ are, independently, hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl of the formula N (R ₁₄₎ (R ₁₅ each Amines of (R ₁₆ ); (iii) a 6 membered heterocyclic base wherein at least 1 is nitrogen, such as, for example, pyridine; And (iv) an inorganic base selected from alkali metal carbonates and alkali metal hydroxides, preferably potassium carbonate; The phase transfer catalyst is an alkyl ammonium halide, preferably tetrabutylammonium chloride; The solvent is a polar solvent selected from THF, DMF, dioxane, acetonitrile and mixtures thereof; And The compound of formula R ₁ -CH = CH-COR ₅ is selected from methyl acrylate, ethyl acrylate, acrolein and vinyl methyl ketone How to Obtain Vitamin D Derivatives. The method of claim 1, In said alternative (J), The compound of formula (II) is selected from a compound of formula IIA1, a compound of formula IIA2 and a compound of formula IIA3 according to claim 7; The palladium compound may be tri- t -butylphosphine, tricyclohexylphosphine, 1,1'-bis (di- t -butylphosphine) ferrocene, diphenylphosphino-2- (di- t -butylphosphine Optional selected from palladium acetate or chloride complexed with phosphine ligands selected from ethyl ferrocene, triphenylphosphine, ditriphenylphosphine, tetrakis (triphenylphosphine) and tris (dibenzylidene-acetone) dipalladium Palladium salts, or palladium complexes complexed with; Preferably palladium acetate optionally complexed with tri- t -butylphosphine; The silver salt is selected from silver acetate, silver carbonate and silver nitrate; The solvent is a polar solvent selected from THF, DMF, dioxane, acetonitrile and mixtures thereof, preferably THF; And The compound of Formula R ₁ -CH = C (OH) R ₅ R ₆ is 1-butene-3-ol, 1-penten-3-ol, 3-methyl-1-buten-3-ol, 3-methyl- Selected from 1-penten-3-ol and 1-propene-3-ol How to Obtain Vitamin D Derivatives. The method of claim 1, (a) treating with SO ₂ in a solvent, wherein A forms an SO ₂ adduct of the compound of formula (I) wherein (A2) or (A3), wherein A is (A1) By forming a compound of formula (I) wherein W is SO ₂ ; or, (b) reducing the compound of formula (I) comprising at least one triple bond (n ≧ 1) and a hydroxyl group (Y = OH) in a solvent, optionally in the presence of a base, with a triple-bond reducing agent, By obtaining a compound of formula (I) comprising at least one double bond and one OH group (Y = OH); or, (c) in a solvent, with a carbonyl group reducing agent, wherein D is -C (O) R ₅ to reduce the compound of formula (I) wherein Y is OH to obtain a compound of formula (I) By doing; or, (d) where the compound of formula (I) comprises a group (A2) or (A3), first protected with SO ₂ and then in the solvent, in the presence of a metal catalyst, "≧ 1 or" n "> 1 or" m "and" n "are all ≥ 1 by hydrogenating a compound of formula (I); or, (e) in a solvent, in the presence of a base, heating, adduct breakdown of the compound of formula (I) wherein A is (A1) and W is SO ₂ , wherein A By obtaining a compound of the general formula (I) wherein (A2); or, (f) photochemical isomerization of the compound of formula (I) wherein A is (A2), wherein A is a compound of formula (I) wherein (A3) ; or, (g) reacting with a deprotecting agent, wherein Z and Z 'are deprotection of the compound of formula (I), wherein the compound of formula (I) is a hydroxyl group protected at the same time with a hydroxyl protecting group, Z and Z 'are simultaneously obtained by obtaining a compound of formula (I) Converting the compound of formula (I) to another compound of formula (I) How to Obtain Vitamin D Derivatives. The method of claim 20, In said alternative (a), The solvent is an aprotic organic solvent selected from ether, methylene chloride, benzene and mixtures thereof, preferably methylene chloride How to Obtain Vitamin D Derivatives. The method of claim 20, In alternative (b) above, The triple bond reducing agent is a hydroxide derivative of aluminum selected from Red-Red, LiAlH ₄ , methyl-di- iso - butylaluminum and lithium hydride; The base is a metal alkoxide selected from sodium methoxide, sodium ethoxide and potassium t-butoxide; And The solvent is selected from ethers, aromatic hydrocarbons and mixtures thereof, preferably THF How to Obtain Vitamin D Derivatives. The method of claim 20, In said alternative (c), The carbonyl group reducing agent is a metal hydroxide or an alkyl metal selected from alkyl lithium, alkyl cerium, and organomagnesium How to Obtain Vitamin D Derivatives. The method of claim 23, wherein The carbonyl group reducing agent is LiAlH ₄ , NaBH ₄ , Redal, Alpine-Borane, Dibal (Diisobutylaluminium, diisobutylaluminum), DIP-chloride, Ca (BH ₄ ) ₂ , NaBH ₄ / CeCl ₃ , methyl Selected from lithium and ethyl lithium How to Obtain Vitamin D Derivatives. The method of claim 20, In said alternative (d), The metal catalyst is selected from Pd, Pt and Rh, preferably Pt / C, And the solvent comprises a polar solvent selected from methanol, ethanol, ethyl acetate, DMF and mixtures thereof, optionally mixed with an apolar solvent selected from benzene, toluene and mixtures thereof, preferably, ethanol / benzene mixtures Being How to Obtain Vitamin D Derivatives. The method of claim 20, In said alternative (e), The base is selected from alkali metal carbonates and alkali metal bicarbonates, preferably sodium bicarbonate, And the solvent is a polar solvent selected from methanol, ethanol, isopropanol, butanol, DMF and mixtures thereof, preferably DMF. How to Obtain Vitamin D Derivatives. The method of claim 20, In the alternative (f) above, Wherein the photochemical isomerization of the compound of formula (I) wherein A is (A2) - optionally, wherein R _14, R ₁₅ and R ₁₆ are, independently, hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl of the formula N with each other (R ₁₄₎ In the presence of an amine of (R ₁₅ ) (R ₁₆ ), with diffuse daylight and I ₂ ; or, Optionally with diffused daylight and I ₂ in the presence of a 6 membered heterocyclic base wherein at least 1 is nitrogen; or, With phenyl diselenide and tungsten light; or, Ultraviolet light in the presence of an aromatic photosensitizer. Being performed How to Obtain Vitamin D Derivatives. The method of claim 27, The photochemical isomerization is carried out with UV light, The solvent is toluene, The photosensitizer is an anthracene How to Obtain Vitamin D Derivatives. The method of claim 20, In said alternative (g), In a solvent, optionally in the presence of a phase transfer catalyst, the hydroxyl protecting group is a silyl group and the deprotecting agent is selected from fluorine and alkoxides; or, In a solvent, optionally in the presence of a phase transfer catalyst, said hydroxyl protecting group is an acyl group and said deprotecting agent is an alkoxide or inorganic base How to Obtain Vitamin D Derivatives. The method of claim 29, Wherein the hydroxyl protecting group is a silyl group and the deprotecting agent is tetrabutylammonium fluoride in tetrahydrofuran, or alternatively potassium t -butoxide in DMSO; or, Wherein the hydroxyl protecting group is an acyl group, the deprotecting agent is sodium or potassium hydroxide, and the solvent is ethanol How to Obtain Vitamin D Derivatives. The method of claim 1, The compound of formula (II) A has the same meaning as described above in connection with the compound of formula (I) Compound of Haloform selected from chloroform, bromoform and iodineform, Obtained in the organic solvent by reaction in the presence of a salt or a divalent chromium complex (Cr ²⁺ ) How to Obtain Vitamin D Derivatives. The method of claim 1, The compound of formula (I) obtained is: -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(ethynyl) -9,10-secopregna-5 ( E ),-7 ( E ), 10 (19) -triene (Compound 1), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( S )-(ethinyl) -9,10-secopregna-5 ( E ),-7 ( E ), 10 (19) -triene (compound 1)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(ethynyl) -9,10-secopregna-5 ( Z ),-7 ( E ), 10 (19) -triene (compound 2), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( S )-(ethinyl) -9,10-secopregna-5 ( Z ),-7 ( E ), 10 (19) -triene (compound 2)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3'-oxopropyn-1'-yl) -9,10- Secopregna-5 ( E ),-7 ( E ), 10 (19) -triene (Compound 3), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3'-oxopropyn-1'-yl) -9,10-secopregna-5 ( E ) , -7 ( E ), 10 (19) -triene (compound 3)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3'-oxopropyn-1'-yl) -9,10- Secopregna-5 ( Z ),-7 ( E ), 10 (19) -triene (Compound 4), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3'-oxopropyn-1'-yl) -9,10-secopregna-5 ( Z ) , -7 ( E ), 10 (19) -triene (compound 4)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3 '-( R ) -hydroxypropyn-1'-yl) -9,10-secopregna-5 ( E ),-7 ( E ), 10 (19) -triene (compound 5 ( R )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3 '-( R ) -hydroxypropyn-1'-yl) -9,10-secopregna- 5 ( E ),-7 ( E ), 10 (19) -triene (compound 5 ( R ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3 '-( S ) -hydroxypropyn-1'-yl) -9,10-secopregna-5 ( E ),-7 ( E ), 10 (19) -triene (compound 5 ( S )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3 '-( S ) -hydroxypropyn-1'-yl) -9,10-secopregna- 5 ( E ),-7 ( E ), 10 (19) -triene (compound 5 ( S ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3 '-( R ) -hydroxypropyn-1'-yl) -9,10-secopregna-5 ( Z ),-7 ( E ), 10 (19) -triene (compound 6 ( R )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3 '-( R ) -hydroxypropyn-1'-yl) -9,10-secopregna- 5 ( Z ),-7 ( E ), 10 (19) -triene (compound 6 ( R ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3 '-( S ) -hydroxypropyn-1'-yl) -9,10-secopregna-5 ( Z ),-7 (E), 10 (19) -triene (compound 6 ( S )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( S )-(3'-cyclopropyl-3 '-( S ) -hydroxypropyn-1'-yl) -9,10-secopregna- 5 ( Z ),-7 ( E ), 10 (19) -triene (compound 6 ( S ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( S )-(4'-hydroxy-4'-methylpentin-1'-yl) -9,10-year old Copregna-5 ( E ),-7 ( E ), 10 (19) -triene (compound 7), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( S )-(4'-hydroxy-4'-methylpentyn-1'-yl) -9,10-secopregna-5 ( E ) , -7 ( E ), 10 (19) -triene (compound 7)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-hydroxy-4'-methylpent-1'-ynyl) -9,10-three SO ₂ addition product of copregna-5,7 ( E ), 10 (19) -triene (compound 8), (SO ₂ adduct of 1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-hydroxy-4'-methylpent-1'-ynyl) -9,10-secopregna- 5,7 ( E ), 10 (19) -triene (compound 8)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-hydroxy-3 '( R ) -isopropylpro-pan-1'-yl) -9,10-secopregna-5 ( E ),-7 ( E ), 10 (19) -triene (compound 9 ( R )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-hydroxy-3 '( R ) -isopropylpro-pan-1'-yl) -9,10-secopregna -5 ( E ),-7 ( E ), 10 (19) -triene (compound 9 ( R ))); -1 (S), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-hydroxy-3 '( S ) -isopropylpropane-1'-yl) -9 , 10-Secopregna-5 ( E ),-7 ( E ), 10 (19) -triene (Compound 9 ( S )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-hydroxy-3 '( S ) -isopropylpropan-1'-yl) -9,10-secopregna-5 ( E ),-7 ( E ), 10 (19) -triene (compound 9 ( S ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-hydroxy-4'-methylpentan-1'-yl) -9,10-three Copregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 10), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-hydroxy-4'-methylpentan-1'-yl) -9,10-secopregna-5 ( E ) , 7 ( E ), 10 (19) -triene (compound 10)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-oxo-pentane-1'-yl) -9,10-secopregnna-5, SO ₂ addition product of 7 ( E ), 10 (19) -triene (Compound 11), (SO ₂ adduct of 1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-oxo-pentan-1'-yl) -9,10-secopregna-5,7 ( E ), 10 (19) -triene (compound 11)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-oxopentan-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 12), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-oxopentan-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ) , 10 (19) -triene (compound 12)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(butan-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 13), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(butan-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 ( 19) -triene (compound 13)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-methylpentan-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 14), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-methylpentan-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ) , 10 (19) -triene (compound 14)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-hydroxyl-5'-methylpentan-1'-yl) -9,10-three SO ₂ addition product of copregna-5,7 ( E ), 10 (19) -triene (compound 15), (SO ₂ adduct of 1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-hydroxyl-5'-methylpentan-1'-yl) -9,10-secopregna- 5,7 ( E ), 10 (19) -triene (compound 15)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-oxo-pent-1 '( E ) -enyl) -9,10-secopregnna SO ₂ addition product of -5,7 ( E ), 10 (19) -triene (Compound 16), (SO ₂ adduct of 1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-oxo-pent-1 '( E ) -enyl) -9,10-secopregna- 5,7 ( E ), 10 (19) -triene (compound 16)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(butene-1 '( E ) -yl) -9,10-secopregna-5 ( E ) , 7 ( E ), 10 (19) -triene (compound 17), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(buten-1 '( E ) -yl) -9,10-secopregna-5 ( E ), 7 ( E ) , 10 (19) -triene (compound 17)); -1 (S), 3 (R ) - bis (tert-butyldimethylsilyloxy) -20 (R) - (4'- methyl pentene -1 'E) - yl) -9,10-secopregna -5 ( E ), 7 ( E ), 10 (19) -triene (compound 18), (1 (S), 3 ( R) -Bis (tert -butyldimethylsilyloxy) -20 (R) - (4'-methylpenten-1 'E) -yl) -9,10-secopregna-5 (E), 7 ( E ), 10 (19) -triene (compound 18)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxyprop-1' ( E )- Enyl) -9,10-seco-pregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 19 ( R )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxyprop-1' ( E ) -enyl) -9,10- seco-pregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 19 ( R ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E )- Enyl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 19 ( S )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -9,10- secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 19 ( S ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-dimethyl-3 '( R ) -hydroxypenta-1' ( E ) -enyl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 20 ( R )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-dimethyl-3 '( R ) -hydroxypenta-1` ( E ) -enyl) -9,10- secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 20 ( R ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-dimethyl) -3 '( S ) -hydroxypenta-1' ( E ) -enyl ) -9,10-Secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 20 ( S )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-dimethyl) -3 '( S ) -hydroxypenta-1` ( E ) -enyl) -9,10 -secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 20 ( S ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxyprop-1' ( E )- Enyl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 21 ( R )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxyprop-1' ( E ) -enyl) -9,10- secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 21 ( R ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E )- Enyl) -9,10-seco-pregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 21 ( S )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -9,10- seco-pregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 21 ( S ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( R ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 22 ( R )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( R ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10- secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 22 ( R ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( S ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 22 ( S )), (1 ( S ), 3 ( R) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( S ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10- secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 22 ( S ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-cyclohexyl-3 '( R ) -hydroxyprop-1' ( E )- Enyl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 23 ( R )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-cyclohexyl-3 '( R ) -hydroxyprop-1' ( E ) -enyl) -9,10- secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 23 ( R ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-cyclohexyl-3 '( S ) -hydroxyprop-1' ( E )- Enyl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 23 ( S )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-cyclohexyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -9,10- secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 23 ( S ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( R ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 24 ( R )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( R ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10- secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 24 ( R ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( S ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 24 ( S )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( S ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10- secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 24 ( S ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-cyclohexyl-3 '( R ) -hydroxyprop-1' ( E )- Enyl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 25 ( R )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-cyclohexyl-3 '( R ) -hydroxyprop-1' ( E ) -enyl) -9,10- secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 25 ( R ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-cyclohexyl-3 '( S ) -hydroxyprop-1' ( E )- Enyl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 25 ( S )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-cyclohexyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -9,10- secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 25 ( S ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'dimethyl-3 '( R ) -hydroxypent-1' ( E ) -enyl)- 9,10-Secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (Compound 26 ( R )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'dimethyl-3 '( R ) -hydroxypent-1' ( E ) -enyl) -9,10-secopregna -5 ( Z ), 7 ( E ), 10 (19) -triene (compound 26 ( R ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'dimethyl-3 '( S ) -hydroxypent-1' ( E ) -enyl)- 9,10-Secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (Compound 26 ( S )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'dimethyl-3 '( S ) -hydroxypent-1' ( E ) -enyl) -9,10-secopregna -5 ( Z ), 7 ( E ), 10 (19) -triene (compound 26 ( S ))); -20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxyprop-1' ( E ) -enyl) -1 ( S ), 3 ( R ) -dihydroxy-9,10 -Se-prepregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 27 ( R )), (20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxyprop-1' ( E ) -enyl) -1 ( S ), 3 ( R ) -dihydroxy-9,10-se-copregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 27 ( R ))); -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -1 ( S ), 3 ( R ) -dihydroxy-9,10 Secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (Compound 27 ( S )), (20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -1 ( S ), 3 ( R ) -dihydroxy-9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 27 ( S ))); -20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxyprop-1' ( E ) -enyl) -1 ( S ), 3 ( R ) -dihydroxy-9,10 Se-copregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 28 ( R )), (20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxyprop-1' ( E ) -enyl) -1 ( S ), 3 ( R ) -dihydroxy-9,10-se-copregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 28 ( R ))); -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -1 ( S ), 3 ( R ) -dihydroxy-9,10 Secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 28 ( S )), (20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -1 ( S ), 3 ( R ) -dihydroxy-9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 28 ( S ))); -1 ( S ), 3 ( R ) -dihydroxy-20 ( R )-(3 '( S ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-seco -Pregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 29 ( R )), (1 ( S ), 3 ( R ) -dihydroxy-20 ( R )-(3 '( S ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-seco-pregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 29 ( R ))); -1 ( S ), 3 ( R ) -dihydroxy-20 ( R )-(3 '( S ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-aged Copregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 29 ( S )), (1 ( S ), 3 ( R ) -dihydroxy-20 ( R )-(3 '( S ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 29 ( S ))); -1 ( S ), 3 ( R ) -dihydroxy-20 ( R )-(3 '( S ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-seco -Pregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 30 ( R )), (1 ( S ), 3 ( R ) -dihydroxy-20 ( R )-(3 '( S ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-seco-pregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 30 ( R ))); -1 ( S ), 3 ( R ) -dihydroxy-20 ( R )-(3 '( S ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-aged Copregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 30 ( S )), (1 ( S ), 3 ( R ) -dihydroxy-20 ( R )-(3 '( S ) -hydroxy-4'-methylpent-1' ( E ) -enyl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 30 ( S ))); -1 ( S ), 3 ( R ) -bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxy-prop-1' ( E ) -enyl)- 9,10-Secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (Compound 31 ( R )), (1 ( S ), 3 ( R ) -Bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxy-prop-1' ( E ) -enyl) -9,10- secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 31 ( R ))); -1 ( S ), 3 ( R ) -bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -9 , 10-Secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (Compound 31 ( S )), (1 ( S ), 3 ( R ) -Bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -9,10-secopregna- 5 ( Z ), 7 ( E ), 10 (19) -triene (compound 31 ( S ))); -1 ( S ), 3 ( R ) -bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxy-prop-1' ( E ) -enyl)- 9,10-Secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 32 ( R )), (1 ( S ), 3 ( R ) -Bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxy-prop-1' ( E ) -enyl) -9,10- secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 32 ( R ))); -1 ( S ), 3 ( R ) -bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -9 , 10-Secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 32 ( S )), (1 ( S ), 3 ( R ) -Bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -9,10-secopregna- 5 ( E ), 7 ( E ), 10 (19) -triene (compound 32 ( S ))); -1 ( S ), 3 ( R ) -bis ( tert- butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxyprop-1' ( E )- Enyl) -9,10-secopregnna-5,7 ( E ), 10 (19) -triene SO ₂ addition product (compound 33 ( R )), (SO ₂ adduct of 1 ( S ), 3 ( R ) -bis ( tert- butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( R ) -hydroxyprop-1' ( E ) -enyl)- 9,10-secopregna-5,7 ( E ), 10 (19) -triene (compound 33 ( R ))); -1 ( S ), 3 ( R ) -bis ( tert- butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E )- Enyl) -9,10-secopregna-5,7 ( E ), 10 (19) -triene SO ₂ addition product (compound 33 ( S )), (SO ₂ adduct of 1 ( S ), 3 ( R ) -Bis ( tert- butyldimethylsilyloxy) -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl)- 9,10-secopregna-5,7 ( E ), 10 (19) -triene (compound 33 ( S ))); -3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( R ) -hydroxy-4'-methylpent-1' ( E ) -enyl), 9,10- Product of SO ₂ addition of cecopregna-5,7 ( E ), 10 (19) -triene (compound 34 ( R )), (SO ₂ adduct of 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( R ) -hydroxy-4'-methylpent-1' ( E ) -enyl), 9,10-secopregna -5,7 ( E ), 10 (19) -triene (compound 34 ( R ))); -3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( S ) -hydroxy-4'-methylpent-1' ( E ) -enyl), 9,10- SO ₂ addition product of cecopreg-na-5,7 ( E ), 10 (19) -triene (compound 34 ( S )), (SO ₂ adduct of 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(3 '( S ) -hydroxy-4'-methylpent-1' ( E ) -enyl), 9,10-secopreg -na-5,7 (E), 10 (19) -triene (compound 34 ( S ))); -1 ( S ), 3 ( R ) -bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '-( R ) -hydroxyprop-1' ( E ) -enyl)- SO ₂ addition product of 9,10-secopregna-5,7 ( E ), 10 (19) -triene (Compound 35 ( R )), (SO ₂ adduct of 1 ( S ), 3 ( R ) -Bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '-( R ) -hydroxyprop-1' ( E ) -enyl) -9 , 10-secopregna-5,7 ( E ), 10 (19) -triene (compound 35 ( R ))); -1 ( S ), 3 ( R ) -bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -9 SO ₂ addition product of 10-seco-pregna-5,7 ( E ), 10 (19) -triene (compound 35 ( S )), (SO ₂ adduct of 1 ( S ), 3 ( R ) -Bis (acetoxy) -20 ( R )-(3'-cyclopropyl-3 '( S ) -hydroxyprop-1' ( E ) -enyl) -9, 10-seco-pregna-5,7 ( E ), 10 (19) -triene (compound 35 ( S ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-phenyl-4'-oxobut-1 '( E ) -enyl) -9,10 Secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (Compound 36), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-phenyl-4'-oxobut-1 '( E ) -enyl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 36)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-cyclopropyl-4'-oxobut-1 '( E ) -enyl) -9, 10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 37), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-cyclopropyl-4'-oxobut-1 '( E ) -enyl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 37)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-oxopent-1 '( E ) -enyl) -9,10-seco-pregna -5 ( E ), 7 ( E ), 10 (19) -triene (compound 38), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-oxopent-1 '( E ) -enyl) -9,10-seco-pregna-5 ( E ) , 7 ( E ), 10 (19) -triene (compound 38)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-hydroxy-4'-methylpent-1 '( E ) -enyl) -9, 10-Secopregna-5 ( E ) -7 ( E ), 10 (19) -triene (Compound 39), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-hydroxy-4'-methylpent-1 '( E ) -enyl) -9,10-secopregna-5 ( E ) -7 ( E ), 10 (19) -triene (compound 39)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-hydroxy-5'-methylhex-3'-yne-1 '( E )- Enyl) -9,10-secopregna-5,7 ( E ), 10 (19) -triene (compound 40), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-hydroxy-5'-methylhex-3'-yn-1 '( E ) -enyl) -9, 10-secopregna-5,7 ( E ), 10 (19) -triene (compound 40)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( R ) -hydroxy-5'-methylhep-3'-yne-1' ( E ) -enyl) -9,10-secopregna-5,7 ( E ), 10 (19) -triene (compound 41 ( R )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( R ) -hydroxy-5'-methylhep-3'-yn-1' ( E ) -enyl) -9,10-secopregna-5,7 ( E ), 10 (19) -triene (compound 41 ( R ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( S ) -hydroxy-5'-methylhep-3'-yne-1' ( E ) -enyl) -9,10-secopregna-5,7 ( E ), 10 (19) -triene (compound 41 ( S )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( S ) -hydroxy-5'-methylhep-3'-yn-1' ( E ) -enyl) -9,10-secopregna-5,7 ( E ), 10 (19) -triene (compound 41 ( S ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-ethyl-5'-hydroxyhep-3'-yne-1 '( E )- Enyl) -9,10-secopregna-5 (E), 7 (E), 10 (19) -triene (compound 42), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-ethyl-5'-hydroxyhep-3'-yn-1 '( E ) -enyl) -9, 10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 42)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( R ) -hydroxyhex-3'-yne-1' ( E ) -enyl) -9,10-secopregna-5,7 ( E ), 10 (19) -triene (compound 43 ( R )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( R ) -hydroxyhex-3'-yn-1' ( E ) -enyl) -9,10- secopregna-5,7 ( E ), 10 (19) -triene (compound 43 ( R ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( S ) -hydroxyhex-3'-yn-1' ( E ) -enyl) -9,10-secopregna-5,7 (E), 10 (19) -triene (compound 43 ( S )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( S ) -hydroxyhex-3'-yn-1' ( E ) -enyl) -9,10- secopregna-5,7 ( E ), 10 (19) -triene (compound 43 ( S ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-ethyl-5'-hydroxyhep-3'-yne-1 '( E )- Enyl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 44), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-ethyl-5'-hydroxyhep-3'-yn-1 '( E ) -enyl) -9, 10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 44)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-ethyl-5'-hydroxyhep-3'-yne-1 '( E )- Enyl) -9,10-secopregna-5,7 ( E ), SO ₂ addition product of 10 (19) -triene (Compound 45), (SO ₂ adduct of 1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-ethyl-5'-hydroxyhep-3'-yn-1 '( E ) -enyl ) -9,10-secopregna-5,7 ( E ), 10 (19) -triene (compound 45)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-oxo-penta-1 '( E ), 3' ( E ) -diene-1 ' -Yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 46), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-oxo-penta-1 '( E ), 3' ( E ) -dien-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 46)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-methoxycarbonylbuta-1 '( E ), 3' ( E ) -diene- 1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 47), (1 ( S ) -3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(4'-metoxycarbonylbuta-1 '( E ), 3' ( E ) -dien-1'-yl) -9 , 10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 47)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-hydroxypenta-1 '( E ), 3' ( E ) -diene-1 ' -Yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 48), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-hydroxypenta-1 '( E ), 3' ( E ) -dien-1'-yl) -9 , 10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 48)); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( R ) -hydroxyhexa-1' ( E ), 3 '( E ) -diene -1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 49 ( R )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( R ) -hydroxyhexa-1' ( E ), 3 '( E ) -dien-1'-yl ) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 49 ( R ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( S ) -hydroxyhexa-1' ( E ), 3 '( E ) -diene -1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 49 ( S )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( S ) -hydroxyhexa-1' ( E ), 3 '( E ) -dien-1'-yl ) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 49 ( S ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( R ) -hydroxyhepta-1' ( E ), 3 '( E ) -diene -1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 50 ( R )), (1 ( S ), 3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( R ) -hydroxyhepta-1' ( E ), 3 '( E ) -dien-1'-yl ) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 50 ( R ))); -1 ( S ), 3 ( R ) -bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( S ) -hydroxyhepta-1' ( E ), 3 '( E ) -diene -1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 50 ( S )), (1 ( S ) -3 ( R ) -Bis ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( S ) -hydroxyhepta-1' ( E ), 3 '( E ) -dien-1'-yl ) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 50 ( S ))); -1 ( S ), 3 ( R ) -bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-hydroxy-5'-methylhexa-1 '( E ),-3' ( E ) -diene-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 51), (1 ( S ), 3 ( R ) -Bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-hydroxy-5'-methylhexa-1 '( E ),-3' ( E ) -dien- 1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 51)); -1 ( S ), 3 ( R ) -bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( R ) -hydroxy-5'-methylhepta-1' ( E ), 3 '( E ) -diene-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 52 ( R )), (1 ( S ), 3 ( R ) -Bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( R ) -hydroxy-5'-methylhepta-1' ( E ), 3 '( E )- dien-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 52 ( R ))); -1 ( S ), 3 ( R ) -bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( S ) -hydroxy-5'-methylhepta-1' ( E ), 3 '( E ) -diene-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 52 ( S )), (1 ( S ), 3 ( R ) -Bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5 '( S ) -hydroxy-5'-methylhepta-1' ( E ), 3 '( E )- dien-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 52 ( S ))); -1 ( S ), 3 ( R ) -bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-ethyl-5'-hydroxyhepta-1 '( E ), 3' ( E ) -Diene-1'-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 53), (1 ( S ), 3 ( R ) -Bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-ethyl-5'-hydroxyhepta-1 '( E ), 3' ( E ) -dien-1 '-yl) -9,10-secopregna-5 ( E ), 7 ( E ), 10 (19) -triene (compound 53)); -1 ( S ), 3 ( R ) -bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-hydroxy-5'-methylhexa-1 '( E ),-3' ( E ) -diene-1'-yl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 54), (1 ( S ), 3 ( R ) -Bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-hydroxy-5'-methylhexa-1 '( E ),-3' ( E ) -dien- 1'-yl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 54)); And -1 ( S ), 3 ( R ) -bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-ethyl-5'-hydroxyhepta-1 '( E ), 3' ( E ) -Diene-1'-yl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 55) (1 ( S ), 3 ( R ) -Bis- ( tert -butyldimethylsilyloxy) -20 ( R )-(5'-ethyl-5'-hydroxyhepta-1 '( E ), 3' ( E ) -dien-1 '-yl) -9,10-secopregna-5 ( Z ), 7 ( E ), 10 (19) -triene (compound 55)) Selected from How to Obtain Vitamin D Derivatives. Use of a compound of formula (II) as defined in claim 1 to obtain a vitamin D derivative of formula (I) as defined in claim 1.